Rhinosinusitis Prevention and Therapy with Proinflammatory Cytokine Inhibitors

ABSTRACT

The disclosure describes an aerosolizer with (i) means sized for intranasal or paranasal insertion that produces an aerosol from a material for delivery in close proximity to the upper airways, and (ii) the material comprising one or more proinflammatory cytokine inhibitor(s).

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application60/819,703 (filed Jul. 11, 2006), U.S. Provisional Application60/878,397 (filed Jan. 4, 2007), and U.S. Provisional Application60/907,027 (filed Mar. 16, 2007), all of which are incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to methods for treating a disease of theupper airways with proinflammatory cytokine inhibitors.

BACKGROUND OF THE INVENTION

Upper airways disease or rhinosinusitis are common disorders with over33 million cases annually in the US. Both acute and chronic forms ofsinusitis are common leading to over 12 million physician visitsannually. Of rhinosinusitis sufferers, up to 500,000 people resort tosinus surgery in the U.S. each year. A recent epidemiological review(Vital Health Statistics, USA, 10:1999) ranks chronic rhinosinusitis asthe most common chronic condition in the U.S. affecting more people thanhypertension and asthma. It has been estimated that the annual cost ofthis condition in the US is $24 billion. These upper airways disordersare characterized by a variety of symptoms, including nasal congestion,facial pain and pressure, nasal discharge, and headaches.

Anatomically, the nasal passageways up to the soft palate and includingthe sinuses can be thought of as the upper airways or upper respiratorytract, while the larynx and below including the lungs, can be thought ofas the lower airways or lower respiratory tract. The sinuses are fourpairs of air-filled spaces, the ethmoid, maxillary, sphenoid, andfrontal sinuses, located in the upper airways. The upper airways,including the sinuses, warm and humidify the air during breathing. Theupper airways filter particles, such as bacteria, spores, and dust, fromthe air. Generally, the nasal passages contain bacteria, while thesinuses are sterile. The upper airways and sinuses are lined with amucosal layer of epithelium, similar in most ways to the mucosalepithelium that lines the lower respiratory tract. The sinusescommunicate with the rest of the upper airways through small orifices orostium that may become obstructed leading to symptoms and disease.

Sinusitis and rhinitis causes inflammation which results in decreasedperfusion of the upper airways by bodily fluids. These sites aredifficult to reach with aerosols or systemic bioactive substances, ascompared to other tissues. Larger systemic doses are required to delivertherapeutically effective amounts of bioactive agents to the upperairways, which increase the likelihood of adverse events. Moreover,inadequate dosing can lead to microbial resistance, spread of disease,and continued suffering of the subject. What are needed in the art areminimally invasive methods which improve the local delivery of a varietyof bioactive agents to nasal passages and paranasal sinuses in order tomore effectively and efficiently treat these disorders.

A typical process leading to acute sinusitis starts with a flu or coldvirus. Viruses themselves do not usually cause sinusitis directly andare implicated in only about 10% of sinusitis cases. Instead, they setthe stage by causing nonallergic inflammation and congestion in theupper airways (called rhinitis) that leads to obstruction. This createsan environment conducive to bacterial growth that can lead to upperairways infection. In fact, rhinitis is the precursor to sinusitis in somany cases that expert groups now refer to most cases of upper airwaysdisease as rhinosinusitis (Guide to First-line Management. Kennedy(1994) Health Communications, Inc.).

The vast majority of rhinosinusitis is not allergic in its origins andis associated with increased levels of nonallergic proinflammatorycytokines such as IL-8, IL-1, and TNF. Rhinosinusitis is oftenassociated with bacterial invasion of the upper airways leading toendotoxin release and increased TNF-alpha. Sun et al. showed that VEGFconcentration was significantly higher in paranasal sinus effusions inresponse either endotoxin or TNF-alpha in biopsies from sinusitissubjects relative to controls. Viral infections can also modulate TNFmediated responses in the upper airways (Sun et al. Auris Nasus Larynx.32(3):243-9(2005)). Das et al. reported, the amplification ofproinflammatory cytokines by respiratory syncytial virus infection inhuman nasal epithelial cells. RSV infection of nasal epithelial cellresulted in significant accumulations of interleukin IL-6, IL-8, andRANTES when compared with findings in control samples. Theseinvestigators concluded that RSV infection primes nasal epithelial cellsto TNF, resulting in a hyperimmune response.

Frequently, rhinosinusitis sufferers will have nasal polyps. Polyps arebenign masses of extra tissue that cause problems related to their sizeand location. Nasal and sinus polyps form commonly in severe or chronicdisease and can obstruct drainage of the nose and sinuses, and inextreme instances, may even protrude from the nose. Nasal polyposis isalso a nonallergic inflammatory condition of the nose and sinusesassociated with chronic nonallergic rhinitis, aspirin intolerance, andnonallergic asthma (Holmberg et al. Clin. Exp. Allergy Suppl. 3:23-30(1996)). For most subjects with nasal polyps, treatment consists of bothmedical and surgical management, as surgery cannot treat the underlyinginflammatory component of the mucosal disease. Other conditionsassociated with nasal polyps are Churg-Strauss Syndrome, fungalsinusitis, and cilia dyskinetic syndrome, (Kartagener's) and YoungSyndrome.

Historically, the treatment of rhinosinusitis has largely focused onaddressing the symptoms of the condition through acute antibiotictherapy, intranasal or oral corticosteroids, and sinus surgery. Whileantibiotics are useful in treating the acute exacerbations ofrhinosinusitis, antibiotics alone often do not eliminate the underlyingoften-chronic inflammation. Moreover, systemic antibiotics are oftenless effective because of poor tissue penetration associated withrhinosinusitis. Intranasal and oral corticosteroids, have been usedextensively to reduce the inflammation that plays a critical role inrhinosinusitis, but corticosteroids can cause serious side effectsincluding thinning of membranes, bleeding, growth retardation inchildren, and osteoporosis; and when possible must be avoided orcautiously used with patients that have certain conditions, such asgastrointestinal ulcers, renal disease, hypertension, diabetes,osteoporosis, thyroid disorders, and intestinal disease.

Anecdotally, some investigators describe patients who get relief oftheir sinus symptoms by flushing their nasal passages with saline.Symptomatic improvement is achieved by clearing mucus and hydratingthick secretions. It may also decrease blood flow resulting indecongestion, and infectious organisms are also removed with the nasalsecretions. Many patients are asked to do this regularly afterendoscopic surgery when catheters are available to facilitate flushing.Commercially available products include saline-filled squeeze atomizers,some of which contain the moisturizing agent glycerol. The nares mayalso be washed with the saline using a bulb or catheter-tipped syringe.Additionally, investigators have reported hypertonic saline can bebeneficial for rehydration. Despite these reports, rehydrating andflushing agents do not treat the underlying inflammation inrhinosinusitis and other problems including pain, infection, viscoussecretions, and polyps.

No convincing data exists to support the use of antihistamines anddecongestants in rhinosinusitis. Some CF patients have been counseled tostay away from them for fear of further drying out secretions.Physicians report that still other CF subjects, especially those with aclear history of allergies, use antihistamines regularly with relief ofsymptoms of stuffiness and ninny nose and no worsening of their lungcongestion.

Decongestants, such as pseudoephedrine (Sudafed), can be helpful forrelieving symptoms of sinus headache or fullness. Topical decongestants,such as oxymetazoline (AFRIN), can give temporary relief by promotingsinus drainage, but should not be used more than three consecutive daysfor fear of a rebound phenomenon leading to increased nasal secretions.Anticholinergic compounds can also be useful in drying and shrinkingmembranes.

Mucolytics, such as guaifenesin and N-acetyl cysteine-depolymerize mucinmolecules and may be used to promote sinus drainage and are thought notto be detrimental (Marks et at. Am. J. Rhinol. 11(1):11-4 (1997)).Numerous nucleases have been described. Nuclease can be divided into twoclasses, exonucleases and endonucleases, based on the positions of thecleaved bonds within the DNA or RNA polymers. One nuclease, DNase has anumber of known utilities and has been used for therapeutic purposes.Its principal therapeutic use has been to reduce the viscoelasticity ofpulmonary secretions in such diseases as pneumonia and cystic fibrosis,thereby aiding in the clearing of the lower respiratory airways(Lourenco et al. Arch. Intern. Med, 142:2299-2308 (1982); Shak et al.Proc. Natl. Acad. Sci., USA. 1990, vol. 87:9188-9192; and Hubbard et al.New England J. Medicine 326(12):812-815 (1992)). The utility ofnucleases in rhinosinusitis is limited however because these agents donot decrease inflammation and nor do they treat the underlying etiologicagent.

Surgeries frequently used in rhinosinusitis to improve sinus drainageare rooted in the theory that the disease can be reversed by identifyingand correcting the obstruction that caused the condition, but while suchsurgery usually offers temporary relief of symptoms, it is typically notcurative.

Cystic Fibrosis (CF) affects the respiratory epithelium causing theinflammation and infection. Virtually all individuals with CF sufferfrom pansinusitis, inflammation, and infection of all their sinuses.Complication of sinusitis in CF can cause significant symptoms and insome eases may contribute to the worsening of lung disease (Ramsey etal. Allergy Clin. Immunol. 90:547-53 (1992); Lewiston et al. Transplant.Proc. 23:1207-8 (1991); Umetsu et al. Lancet 335:1077-8 (1990)).

The true incidence of sinusitis in CF is not known, but in reality,patients with cystic fibrosis always have chronic sinusitis. The greatmajority of patients with CF develop sinus symptoms, usually between theages of 5 and 14 years (Stern et al. Am. J. Dis. Child. 136:1067-70(1982)). Nasal polyps are the most distinctive of the physical findings.Polyps are benign masses of extra tissue that cause problems related totheir size and location. Nasal and sinus polyps form commonly in CF andcan obstruct drainage of the nose and sinuses, and in extreme instances,may even protrude from the nostrils. The prevalence of nasal polyps inCF has been reported as high as 48% and appears to be proportional toage (Brihaye et al. Int. J. Pediatr. Otorhinolaryngol 28:141-3 (1994);Caste Rhinology 33:152 (1995)).

It is generally accepted that there is some penetration of the sinuseswith orally inhaled tobramycin for patients who use the drug regularly.Anecdotally, many CF patients have benefited from this form oftreatment. However, commercial nebulizers are designed to produceaerosols with a particle distribution to maximize deposition of drug inthe lower airways.

As in other subjects with rhinosinusitis, nasal steroids are used amainstay of therapy for CF sufferers of rhinosinusitis also. There arereports that regular use of nasal steroids diminish the size and numberof nasal polyps, and that use after polypectomy decreases the rate atwhich polyps reform (Hui et al. Eur. Arch. Otorhinolaryngol 252:191-6(1995)).

The surgical options include placement of antrostomies, debridement ofmaxillary sinuses, ethmoidectomies, and nasal polypectomy. Surgicalintervention may relieve nasal obstruction, decrease purulent nasaldischarge, increase activity level, and improve olfaction (Nishioka etal. Orolaryngol. Head Neck Surg. 113:440-5 (1995)). In addition, sinussurgery without aggressive follow-up medical care, such as upper airwayclearance measures or inhaled corticosteroids, is not useful (Mak et al.Clinical Reviews in Allergy and Immunology 21:51-63 (2001)).

Another major current limitation in treating rhinosinusitis is theinability to achieve sufficient drug levels in these inflamed tissues.While a variety of catheters, microcatheters and cannulae are used inprocedures to deliver fluid, gas, suction and energy to select regionsof the body, none have been employed effectively in treatingrhinosinusitis. Existing catheters are typically straight or curvedsegments of rigid plastic or metal tubing attached to a connector. Inthe development of advanced less invasive methods to treat the rhinitis,sinusitis, and sine-nasal polyps, it is desired to have microcathetersthat can access and be advanced into very small structures or the ostiumof a paranasal sinus to perform minimally invasive procedures includingthe delivery of beneficial bioactive materials including therapeutics.What are needed are microcatheters that access curved or tortuous spacessuch as the entrances to the various sinuses. Such a device will requirea combination of flexibility and rigidity in order to be advanced to thetarget site, while maintaining a diameter in the range of 50 to 1500microns.

SUMMARY OF THE INVENTION

The invention provides for glycols, glycerin, pro cytokine inhibitor,pharmaceutically acceptable carrier, and a delivery device capable ofexpressly delivering said compositions to the upper airways. Thecompositions may contain a single active ingredient such as aproinflammatory cytokine inhibitor that may be administered to themammal in need of treatment, or alternatively, may contain one or moreadditional pharmacologic agents capable of reducing inflammation,secretions, infection, pain, or hydrating secretions. The invention alsoprovides methods for formulating a composition containing aproinflammatory cytokine inhibitor with an effective amount of one ormore pharmacologic agents such as e.g., anti-inflammatory agents,antibiotics, antifungals, antivirals, steroids, pain relievers,surfactants, hydrating agents, vaccines, and other pharmacologicallyactive and inactive compounds.

The method of treating upper airway disease, in accord with theinvention, comprises administering a therapeutically effective amount ofa composition comprising one or more inflammatory cytokine inhibitors.In one embodiment, the inhibited proinflammatory cytokine is TNF, IL-1,or IL-8. The proinflammatory cytokine inhibitor composition isadministered in an amount sufficient to inhibit inflammation in theupper airways. Advantageously, a therapeutically or prophylacticallyeffective amount of the composition is typically in the range of 0.1 mgto 100 mg daily, administered in single or divided doses. Thecomposition may be administered in spray, aerosol, gel, solution,emulsion or suspension form. As another aspect, the method ofadministration of the composition may be perioral, intranasal, topical,or parenteral. The composition may be applied directly to the upperairways or the paranasal sinuses via microcatheter.

In accordance with another aspect of the invention, a medicationdispensing unit comprises a receptacle having a first and second end.The composition within the receptacle comprises a therapeuticallyeffective amount of proinflammatory cytokine inhibitors and apharmaceutically acceptable carrier. There is a label overlying thereceptacle. A further object of the invention is to distribute theeffective amount of proinflammatory cytokines directly to the upperairways. Therefore, the invention may comprise a microcatheter, aliquid-pressure type sprayer, and a one-way valve delivery systemassembly. In some embodiments, the microcatheter has an outer diameterof 1,000 microns or less.

The method of treatment and medication dispensing unit of the inventioneffectively treat conditions of the upper airway by targetingtraditionally inaccessible sites of disease. This results in reduceddosage requirements, important factors in the safe and efficientadministration of proinflammatory cytokine inhibitors.

The present invention also discloses microcatheters that are constructedwith as simple single lumen design, multiple components in a compositedesign, microcatheter for powder delivery, and microcatheter sprays. Thecurrent invention teaches methods of use for various microcatheters todeliver bioactive agents to the nasal passages and the paranasal sinusesby minimally invasive means.

DETAILED DESCRIPTION

The present invention provides compositions and methods for treatingupper airway disorders comprising a proinflammatory cytokine inhibitor,one or more active compounds when appropriate, and pharmaceuticallyacceptable carrier, collectively referred to hereinafter as the“composition”, and a delivery device. It is also contemplated that thecomposition will be particularly useful for the treatment of mammalshaving a pathological condition that is accompanied by inflammation ofthe upper airways, abnormal, viscous, or inspissated mucus secretions.Examples of such conditions include but are not limited to acute,subacute or chronic upper airways disease or rhinosinusitis (bacterialinfections, fungal infections, viral infections, clamydial infections,and nonspecific inflammation), nasal surgery, Churg-Strauss syndrome,immune deficiencies, and cystic fibrosis.

The present invention also relates generally to methods of preparationof liquid solutions of proinflammatory cytokine inhibitors that areprotected from thermally induced aggregation of the cytokine inhibitorcomponent. The present invention relates additionally to the generalpreparation of liquid solutions of proinflammatory cytokine inhibitorthat are maintained stable at neutral pH or less than neutral pH, andmost preferred at room temperature or controlled room temperature.

The present invention is also directed to the preparation offormulations that are stable to thermally induced aggregation in liquidsolutions for nucleases (including all of their biologically activeforms, as noted herein). The current invention is directed to acomposition including but not limited to a proinflammatory cytokineinhibitor, and when appropriate, one or more additional therapeuticallyeffective compounds capable of treating rhinosinusitis; a deliverydevice for expressly distributing said composition to the upper airwaysto control inflammatory and when appropriate treat other problemsassociated with rhinosinusitis including pain, inflammation, infection,viscous secretions and polyps.

Although not being bound by any particular theory, it is presentlybelieved that embodiments of the present invention can be used toimprove substantially the sinus drainage, infection, inflammation, pain,and functions, thereby treating pathologic conditions associated withsinus diseases.

DEFINITIONS

Cytokines are regulatory proteins produced in response to certainstimuli that act on receptors on the membrane of target cells. Theseregulatory proteins are generally described in references such asCytokines, A. Mire-Sluis and R. Thorne, ed., Academic Press, New York,(1998).

The term “proinflammatory cytokine” refers to cytokines that generallypromote inflammatory processes including but not limited to IL-6, IL-8,TNF, and IL-1 that differ from allergic cytokines in their structure andfunctions. These proinflammatory cytokines are further described asTNF-Homo Tumor necrosis factor; p55; p60; p75; p80; TNF-R1; TNF-R2;CD120b; Etanercept (contains: Tumor necrosis factor binding protein 2 orMPH); IL-1 alpha; Hematopoietin-1; Antigen CD121a; Antigen CD121b; andinclude those proteins disclosed under GenBank Accession No. P01375,P06804, P19438, P25118, P20333, P25119, P01583, P01582, P14778, P13504,P27-930, and P27931.

As defined herein, the term “proinflammatory cytokine inhibitor(s)” or“proinflammatory cytokine antagonist” includes a “tumor necrosis factorneutralizing antibody”, “TNF antagonist”, “TNF antibody”, “TNF-alphaantibody”, “TNF-beta antibody”, “TNF inhibiting antibody”, “TNFinhibitor”, “IL-6 inhibitor”, “IL-6 antibody”, “IL-6 antagonist”, “IL-8inhibitor”, “IL-8 antibody”, “IL-8 antagonist”, “IL-1 inhibitor”, “IL-1antibody”, “IL-1 antagonist”, “IL-1 receptor antagonist”, “anti-IL-1receptor antibody”, “TNF-alpha receptor antagonist”, “anti-TNF-alphareceptor antibody,” “soluble IL-1 receptor”, “soluble TNF-alphareceptor”, “IL-1 mutein”, “TNF alpha mutein, “IL-1 RNAi”, “TNF-alphaRNAi” or fragment of any of the foregoing is a compound that candecrease, inhibit, block, abrogate, interfere, prevent a proinflammatorycytokine production and/or synthesis, membrane cleavage, release,receptor signaling, or in general inhibit the activity, including one ormore forms of the proinflammatory cytokine.

The terms as used herein incorporate “mature”, “pre”, “pre-pro”, “pro”,“fragments” and “variant” forms of a protein, purified from a naturalsource, chemically synthesized or recombinantly produced.

Multiple human proinflammatory cytokine variants have bean described andin certain instances, proinflammatory cytokine inhibitors that recognizethese variants. It will be understood that natural allelic variationsexist and can occur among individuals, as demonstrated by one or moreamino acid differences in the amino acid sequence of each individual.Allelic variations are specifically encompassed herein. Moreover,fragments either naturally occurring or engineered with all,substantially all, or a significant portion of proinflammatory cytokineinhibitor activity where the proinflammatory cytokine inhibitor may behelpful as a treatment of upper airways disease, are also encompassedherein.

The term “upper airways” or the “upper respiratory tract” when usedherein refers to or describes the anatomic regions including thepassageways from nares or nostrils to the soft palate and includes thesinuses. The term “upper airways” or “upper respiratory tract”specifically incorporates one or more sinuses.

The term “lower airways” or “lower respiratory tract” when used hereinrefers to or describes the anatomic regions below the larynx includingthe trachea and lungs.

The term “pharynx” or “posterior pharynx” when used herein refers to ordescribes the anatomic regions above the trachea and up to the softpalate, but excludes the upper airways.

The term “sinus” or “sinuses” or “paranasal sinuses” when used hereinrefers to or describes the anatomic region including the respiratoryepithelial lined cavities referred to as the frontal sinus or sinuses,maxillary sinus or sinuses, sphenoid sinus or sinuses and ethmoid sinusor sinuses.

The term “rhinosinusitis”, “upper airways disorders”, “upper airwaysdisease”, “upper respiratory tract disorders”, “upper respiratory tractdisease”, and “sinusitis” refers to inflammatory disorders of the upperairways or the upper respiratory tract that are largely nonallergic inorigin.

The term “cystic fibrosis” or “CF” when used herein refers to ordescribes the physiological and pathologic condition in mammalstypically characterized by viscous mucus secretions that tend toobstruct or occlude various internal passageways in a mammal, includingbut not limited to, the sinuses, lower airways, pancreatic ducts, bileducts, and intestinal tract. This condition is typically associated witha genetic variant of the cystic fibrosis transmembrane receptor gene andprotein.

The terms “treating”, “treatment,” and “therapy” as used herein refer tocurative therapy, prophylactic therapy, and preventative therapy.

The term “mammal” as used herein refers to any animal classified as amammal, including humans, cows, horses, dogs, and cats. In a preferredembodiment of the invention, the mammal is a human.

As used herein, “a” or “an” means at least one, unless clearly indicatedotherwise. The term “about”, unless otherwise indicated, refers to avalue that is no more than 10% above or below the value being modifiedby the term. For example, the term “about 5% (w/w)” means a range offrom 4.5% (w/w) to 5.5% (w/w).

As used herein, unless indicated otherwise, the terms “compound” and“compound of the invention” refers to a substance within the compositionof the invention including proteins and small molecules.

As used herein the terms “proinflammatory cytokine inhibitor(s)”, “TNFantagonist(s)”, “TNF inhibitor(s)”, “cytokine inhibitor(s)” or “cytokineantagonists)”, or “inhibitor(s)” according to the present inventionrefers to one or more agents (i.e., molecules or compounds) that inhibitor block the activity of TNF, IL-1, IL-6 or IL-8. The term “antagonist”is used synonymously with the term “inhibitor.” The antagonists of thepresent invention act by blocking or reducing cytokine signaltransduction, or by reducing or preventing expression of the cytokine orits receptor. Antagonists include agents that hind to the cytokineitself, and compounds that bind one or more subunits of the cytokinereceptor. For example, inhibitors include antagonistic antibodies orantibody fragments including single chain antibodies that bind thecytokine itself, antagonistic antibodies or antibody fragments that bindone or more subunits of the cytokine receptor, soluble ligands that bindto the receptor, soluble receptors that bind to the cytokine, as well asaptamers, small molecules, peptidomimetics, and other inhibitory agentscapable of binding the cytokine or its receptor. Antagonists alsoinclude molecules that reduce or prevent expression of the cytokine, itsreceptor, or a receptor subunit. These antagonists include antisenseoligonucleotides that target mRNA, and interfering messenger RNA.Additional antagonists include compounds that prevent and/or inhibitproinflammatory cytokine synthesis, their release or their actions ontarget cells, such as thalidomide, tenidap, phosphodiesterase inhibitors(e.g., pentoxifylline and rolipram), A2b adenosine receptor agonists andA2b adenosine receptor enhancers; compounds which prevent and/or inhibitproinflammatory cytokine receptor signaling, such as mitogen activatedprotein (MAP) kinase inhibitors; compounds which block and/or inhibitmembrane proinflammatory cytokine cleavage, such as variousmetalloproteinase inhibitors; compounds which block and/or inhibitproinflammatory cytokine activity, such as angiotensin converting enzyme(ACE) inhibitors (e.g., captopril), macrolides and ketolides such ase.g., tacrolimus (Rapamune), cyclosporin; and compounds which blockand/or inhibit certain proinflammatory cytokines production and/orsynthesis, such as ERK or MAP kinase inhibitors.

Additional nonlimiting examples of specific proinflammatory cytokineantagonists are known and are incorporated in their entirety herein.Those include e.g., entanercept (ENBREL), sTNF-RI, onercept, D2E7, andRemicade, and antibodies specifically reactive with TNF-alpha andTNF-alpha receptor. Antagonists include IL-1 antagonists includingIL-1ra molecules such as anakinra, KINERET, and IL-1ra-like moleculessuch as IL-1-1Hy1 and IL-1Hy2; IL-1 “trap” molecules as described inU.S. Pat. No. 5,844,099; IL-1 antibodies; solubilized IL-1 receptor,polypeptide inhibitors to IL-1 alpha and IL-1 alpha receptor; andanti-IL-8 antibodies (e.g., ABX-IL-8 (Abgenix)). Other exemplarysuitable IL-1 inhibitors include CDP 484 (IL-1 Ab-PEG) (Celltech/UCB),ACZ885 (IL-1b Ab) (Novartis), Hu007 (IL-1b Ab) (Lilly), and AMG-108(IL-1R Ab) (Amgen).

As used herein, unless indicated otherwise, the term “drug substance”refers to one or more “active ingredients” or “compounds includingbiologics” that are intended to furnish pharmacological activity orother direct effect in the diagnosis, curt, mitigation, treatment, orprevention of disease or to affect the structure or any function of thehuman body such as e.g., a proinflammatory cytokine antagonist.

As used herein, unless indicated otherwise, the terms “composition” and“composition of the invention”, are used interchangeably. Unless statedotherwise, the terms are meant to encompass, and are not limited to,pharmaceutical compositions and nutraceutical compositions containingdrug substance. The composition may also contain one or more“excipients” that are “inactive ingredients” or “compounds” devoid ofpharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease or to affect thestructure or any function of the human body.

As used herein, the term “natural source” refers to a material thatoccurs in the natural environment, or biologic manufactured substancesin a host organism and may comprise one or more biological entities. Forexample, a natural source can be a plant, an animal, an anatomical partof a plant or animal, a microorganism, a mixture of different plants,animals, and/or microorganisms, or an environmental sample. It is notnecessary that the biological entities present in a natural source beclassified or characterized. The term also refers to compositions thathave been prepared directly from that which occurs in the naturalenvironment by a process that does not selectively remove or retain oneor more specific compounds relative to the other different compounds.

It is contemplated that, where the compound(s) of the invention occur ina natural source, the terms “composition” and “composition of theinvention” may encompass a physically and/or chemically modified form ofthe natural source or host organism. For example, if the compound(s) canbe obtained from an organism, the terms are not intended to encompassthe organism or an anatomical part of the organism, however, as powderor a solvent extract of the organism or organism part(s) can be acompound of the invention or compound of the composition of theinvention herein.

Pharmaceutical Compositions

The present invention provides compositions and methods for treatingupper airway disorders with a composition comprising a proinflammatorycytokine inhibitor. The composition may further comprise apharmaceutically acceptable carrier, and a delivery device. Thecomposition is particularly useful for the treatment of mammals having apathological condition that is accompanied by abnormal, viscous, orinspissated mucus secretions or fluid absorption by upper airway cells.Examples of such conditions include but are not limited to acute,subacute or chronic upper airways disease or rhinosinusitis (bacterialinfections, fungal infections, viral infections, clamydial infections,allergic inflammation, and nonspecific inflammation), nasal surgery,Churg-Strauss syndrome, immune deficiencies, and cystic fibrosis.

Exemplary proinflammatory cytokine inhibitors include proteins,polypeptides, peptides, fusion proteins, antibodies (e.g., human,humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab fragments,F(ab)₂ fragments, and antigen-binding fragments thereof) such asantibodies that immunospecifically bind to TNF, IL-6, IL-8 or IL-1,nucleic acid molecules (e.g., antisense molecules or triple helices),organic molecules, inorganic molecules, and small molecules that block,reduce, inhibit or neutralize a function, an activity and/or theexpression of TNF, IL-6, IL-8. The proinflammatory cytokine inhibitormay be an antibody, protein, or small molecule.

In one embodiment, the proinflammatory cytokine inhibitor is an anti-TNFhuman antibody that can bind. TNF-alpha such as e.g., anti-TNFantibodies, antigen-binding fragments thereof, and specified variants orfragments thereof that bind specifically to TNF.

Additional TNF antagonists suitable for compositions, combinationtherapy, co-administration, devices and/or methods of the presentinvention, include, but are not limited to receptor molecules which bindspecifically to TNF; compounds which prevent and/or inhibit TNFsynthesis, TNF release or its action on target cells, such asthalidomide, tenidap, phosphodiesterase inhibitors (e.g., pentoxifyllineand rolipram), A2b adenosine receptor agonists and A2b adenosinereceptor enhancers; compounds which prevent and/or inhibit TNF receptorsignaling, such as mitogen activated protein (MAP) kinase inhibitors;compounds which block and/or inhibit membrane TNF cleavage, such asvarious metalloproteinase inhibitors; compounds which block and/orinhibit TNF activity, such as angiotensin converting enzyme (ACE)inhibitors (e.g., captopril); and compounds which block and/or inhibitTNF production and/or synthesis, such as ERIC or MAP kinase inhibitors.

Other suitable TNF antagonists are macrolide and ketolides, includingantibiotics and nonantibiotic forms. The macrolides are a group of drugs(typically antibiotics) whose activity stems from the presence of amacrolide ring, a large lactone ring to which one or more deoxy sugars,usually cladinose and desosamine, are attached. The lactone ring can beeither 14, 15 or 16-membered. Macrolides belong to the polyketide classof natural products.

The composition may contain one or multiple proinflammatory cytokineantagonists. In various embodiments, a cytokine antagonist reduces thefunction, activity and/or expression of a proinflammatory cytokine by atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 15%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95% or at least 99% relative to acontrol such as phosphate buffered saline (PBS).

The present invention also encompasses formulations that are stable tothermally induced aggregation in liquid solutions for nucleases(including all of their biologically active forms, as noted herein).

Examples of antibodies that immunospecifically bind to TNT-alphainclude, but are not limited to, D2E7 (Abbott Laboratories/KnollPharmaceuticals Co.); CDP571 which is also known as HUMICADE and CDP-870(both of Celltech/Pharmacia); infliximab (REMICADE; Centacor), andTN3-19.12 (Thorbecke et al. Proc. Natl. Acad. Sci. USA 89:7375-7379(1992); Williams et al. Proc. Natl. Acad. Sci. USA 91: 2762-2766(1994)). The additional antibodies that immunospecifically bind toTNF-alpha disclosed in the U.S. Pat. Nos. 5,136,021; 5,147,638;5,223,395; 5,231,024; 5,334,380; 5,360,716; 5,426,181; 5,436,154;5,610,279; 5,644,034; 5,656,272; 5,658,746; 5,698,195; 5,736,138;5,741,488; 5,808,029; 5,919,452; 5,958,412; 5,959,087; 5,968,741;5,994,510; 6,036,978; 6,114,517; and 6,171,787; all or each of which areherein incorporated by reference in their entirety. Examples of solubleTNF-alpha receptors include, but are not limited to, sTNF-R1 (Amgen),etanercept (ENBREL; AMGEN) and its rat homolog RENBREL, solubleinhibitors of TNF-alpha derived from TNFrI, TNFrII (Kohno et al. Proc.Natl. Acad. Sci. USA 87:8331-8335 (1990)), and TNF-alpha (Seckinger etal. Proc. Natl. Acad. Sci. USA 87:5188-5192 (1990); Kohno et al.(1990)).

In another embodiment, a soluble proinflammatory cytokine receptor isused in the compositions and methods of the invention. In a specificembodiment, a TNF-alpha inhibitor used in the compositions and methodsof the invention is etanercept (ENBREL; AMGEN) or a fragment, derivativeor analog thereof. In another embodiment, an antibody thatimmunospecifically binds to TNF-alpha that is a TNF-alpha inhibitor isused in the compositions and methods of the invention. In a specificembodiment, a TNF-alpha antagonist used in the compositions and methodsof the invention is infliximab (REMICADE; Centacor) a derivative, analogor antigen-binding fragment thereof.

Other suitable TNF-alpha antagonists include, but are not limited to,thalidomide (Celgene), antisense molecule 104338 (ISIS), IL-10,quinacrine (mepacrine dichlorohydrate), the murine product TBP-1(Serono(Yeda)), the vaccine CytoTAb (Protherics), the peptide RDP-53(SangStat), CDC-801 (Celgene), DPC-333 (Dupont), VX-745 (Vertex),AGIX-4207 (AtheroGenics), ITF-2357 (Italfarmaco), NPI-13021-31 (Nereus),SCIO-469 (Scios), TACE targeter (Immunix/AHP), CLX-120500 (Calyx),Thiazolopyrim (Dynavax), auranofin (Ridaura) (SmithKline BeechamPharmaceuticals), TNFR-IgG (Ashkenazi et al. 1991, Proc. Natl. Acad.Sci. USA 88:10535-10539), tenidap (Enablex), and anti-p38 MAPK agents.

Additional suitable TNF-alpha antagonists include macrolide antibiotics,such as e.g., erythromycin azithromycin (Zithromax, Zitromax),clarithromycin (Biaxin), dirithromycin (Dynabac), roxithromycin (Rulid,Surlid), developmental macrolides, such as e.g., carbomycin A,josamycin, kitasamycin, oleandomycin, spiramycin, troleandomycin,tylosin/tylocine (Tylan), midecamicine/midecamicine acetat, ketolides,such as e.g., telithromycin (Ketek), cethromycin, spiramycin, ansamycin,oleandomycin, carbomycin and tylocine, and non-antibiotic macrolides,such as e.g., tacrolimus (Rapamune).

The composition useful in the practice of the present invention can beprepared in a number of ways. For instance, the composition can beprepared using an isolated or purified form of proinflammatory cytokineinhibitor. Methods of isolating and purifying proinflammatory cytokineinhibitor from natural sources are known in the art. Alternatively,proinflammatory cytokine inhibitor can be chemically or biologicallysynthesized and prepared using recombinant DNA techniques that are wellknown in the art. These isolation and purification methods can beemployed for obtaining proinflammatory cytokine inhibitor from varioustissues, recombinant manufacturing processes, and transgenic animals.

The proinflammatory cytokine inhibitor may be from human or anynon-human species. For instance, a mammal may have administeredproinflammatory cytokine inhibitor from a different mammalian species(e.g., rats can be treated with human proinflammatory cytokineinhibitor). Preferably, however, the mammal is treated with homologousproinflammatory cytokine inhibitor (e.g., humans are treated with humanproinflammatory cytokine inhibitor) to avoid potential immune reactionsto the proinflammatory cytokine inhibitor. More preferred is when themammal is treated with a proinflammatory cytokine inhibitor with atleast 80% homology to the native proinflammatory cytokine inhibitor orfragment. Still more preferred is when the mammal is treated with aproinflammatory cytokine inhibitor with at least 90% homology to thenative proinflammatory cytokine inhibitor or fragment. Still morepreferred is when the mammal is treated with a proinflammatory cytokineinhibitor or fragment with at least 95% homology to the nativeproinflammatory cytokine inhibitor. Most preferred is when the mammal istreated with a proinflammatory cytokine inhibitor or fragment with 99%or greater homology to the native source of protein.

The present invention also is directed to the stabilization (preventingor minimizing thermally or mechanically induced soluble or insolubleaggregation and/or precipitation of an inhibitor protein) of liquidsolutions containing a proinflammatory cytokine inhibitor at neutral pHor less than neutral pH by the use of surfactants with or without sugarsand divalent cations resulting in clear or nearly clear solutions thatare stable at room temperature or preferred for pharmaceuticaladministration.

The present invention also incorporates the use of amino acids, such ase.g. glycine or proline, as well as divalent cations as a method ofminimizing or inhibiting proinflammatory cytokine inhibitor deamidationof neutral or acidic pH of less than neutral such that deamidation isdeterred or inhibited.

One embodiment is a composition suitable for administration to the upperairways containing a proinflammatory cytokine inhibitor, 0.1% (w/w) ofXylometazoline Hydrochloride, and a film-forming agent. Anotherembodiment is a composition suitable for administration to the upperairways containing a proinflammatory cytokine inhibitor, 0.1% (w/w) ofXylometazoline Hydrochloride, and chlorhexidine digluconate as apreservative. An alternate embodiment is a composition suitable foradministration to the upper airways containing a proinflammatorycytokine inhibitor, 0.1% (w/w) of Xylometazoline hydrochloride andcetylpyridinium chloride as a preservative. Yet another embodiment is acomposition suitable for administration to the upper airways containinga proinflammatory cytokine inhibitor, 0.1% (w/w) of Xylometazolinehydrochloride and benzoxonium chloride as a preservative. A furtherembodiment is a composition suitable for administration to the upperairways containing a proinflammatory cytokine inhibitor, 0.1% (w/w) ofXylometazoline hydrochloride and Methyl 4-Hydroxybenzoate as apreservative. Yet another embodiment is a composition suitable foradministration to the upper airways containing a proinflammatorycytokine inhibitor, and 0.05% (w/w) of Oxymetazoline hydrochloride.

The composition may further comprise nucleic acid molecules encodingproteins, polypeptides, or peptides with proinflammatory cytokineantagonist activity, or proteins, polypeptides, or peptides withcytokine antagonist activity. In one embodiment, nucleic acid moleculesencoding proteins, polypeptides, or peptides with proinflammatorycytokine antagonist activity, or proteins, polypeptides, or peptideswith cytokine antagonist activity can be administered to a subject withrhinosinusitis (e.g., whereby the disorder is prevented, managed,treated or ameliorated by reducing or inhibiting production of NO andexpression of iNOS, IL-8, IL-6, IL-1, and/or TNF). Further, nucleic acidmolecules encoding derivatives, analogs, fragments or variants ofproteins, polypeptides, or peptides with cytokine antagonist activity,or derivatives, analogs, fragments or variants of proteins,polypeptides, or peptides with cytokine antagonist activity can beadministered to a subject in need of treatment in accordance with themethods of the invention. Preferably, such derivatives, analogs,variants, and fragments retain the cytokine antagonist activity of thefull-length, wild-type protein, polypeptide, or peptide.

In another embodiment, agents that are commercially available and knownto function as cytokine antagonists are used in the compositions andmethods of the invention. The proinflammatory cytokine antagonistactivity of an agent can be determined in vitro and/or in vivo by anytechnique well known to one skilled in the art. However, proteins,polypeptides, or peptides that can be used as proinflammatory cytokineinhibitors can be produced by any technique well known in the art ordescribed herein. Proteins, polypeptides, or peptides with cytokineantagonist activity can be engineered to increase the in vivo half-lifeof such proteins, polypeptides, or peptides utilizing techniques wellknown in the art.

An exemplary suitable antibody is chimeric antibody cA2. As described inU.S. Pub. App. 20030143603, chimeric antibody cA2 consists of theantigen binding variable region of the high-affinity neutralizing mouseanti-human TNFalpha IgG1 antibody, designated A2, and the constantregions of a human IgG1, kappa immunoglobulin. The human IgG1 Fc regionimproves allogeneic antibody effector function, increases thecirculating serum half-life, and decreases the immunogenicity of theantibody. The avidity and epitope specificity of the chimeric antibodycA2 is derived from the variable region of the murine antibody A2. In aparticular embodiment, a preferred source for nucleic acids encoding thevariable region of the murine antibody A2 is the A2 hybridoma cell line.

In one embodiment of the invention, the pro-inflammatory cytokineantagonist is an antibody which has high specifity and affinity for TNF,IL-6, IL-8 or IL-1. Methods for determining such specifity and affinityare well-know in the art. See Sambrook et al. A Laboratory Manual, ColdSpring Harbor Laboratory Press; Colligan et al. eds., Current Protocolsin Immunology, Greene Publishing Assoc. and Wiley Interscience, NewYork, (1992-2000); Kozbor et al. Immunol. Today, 4:72-79 (1983); Ausubelet al. eds. Current Protocols in Molecular Biology, Wiley Interscience,New York (1987-2000); and Muller, Meth. Enzymol., 92:589-601 (1983).

Exemplary suitable monoclonal proinflammatory cytokine inhibitors suchas e.g., TNF antibodies are disclosed in U.S. Pat. No. 5,231,024; Molleret al. Cytokine 2(3): 162-169 (1990); WO 91/02078; EP 0218868; EP0288088; Liang et al. Biochem. Biophys. Res. Comm. 137:847-854 (1986);Meager et al. Hybridoma 6:305-311 (1987); Fetidly et al. Hybridoma6:359-369 (1987); Bringman et al. Hybridoma 6:489-507 (1987); Hirai etal. 3. Immunol. Meth. 96:57-62 (1987) and Moller et al. Cytokine2:162-169 (1990) all of which are incorporated in their entirety hereinby reference.

In a preferred embodiment of the current invention, to optimize mucosalactivity of a neutralizing antibody, a Fab fragment is preferred fortopical dosing. Using a Fab fragment minimize epithelial transfer (orsystemic uptake) that is largely dependent on the Fc region of IgG1, andminimizes the recruitment of inflammatory cells and complementactivation. In addition, monoclonal IgM and IgA antibodies may also beproduced that are better tolerated as topical reagents with minimaleffector functions and minimizing immunogenicity and maximizinghalf-life in the tissues.

Another preferred embodiment of the present invention is the use ofproinflammatory cytokine receptor molecules including those that bindproinflammatory cytokines with high affinity and low immunogenicity (seeSchall et al. Cell 61:361-370 (1990). Loetscher et al. Cell 61:351-359(1990); WO 92/07076, which are entirely incorporated herein byreference). The 55 kDa (p55 TNF-R) and the 75 kDa (p75 TNF-R) TNF cellsurface receptors are particularly useful in the present invention. Alsouseful in the present invention are truncated Forms of these receptors,comprising the extracellular domains (ECD) of the receptors orfunctional portions thereof (Corcoran et al. Eur. Biochem. 223:831-840(1994). Truncated forms of the TNF receptors, comprising the ECD, havebeen detected in urine and serum as 30 kDa and 40 kDa. TNFalphaInhibitory binding proteins (Engelmann et al. J. Biol. Chem.265:1531-1536 (1990)) in yet another preferred embodiment, TNF receptormolecules that can be used in the invention are characterized by theirability to treat subjects for extended periods with good to excellentalleviation of symptoms and low toxicity. Low immunogenicity and/or highaffinity, as well as other undefined properties, can contribute to thetherapeutic results achieved.

Proinflammatory receptor multimeric molecules and proinflammatorycytokine immunoreceptor fusion molecules, and derivatives and fragmentsor portions thereof, are additional examples of molecules that areuseful in the methods and compositions of the present invention.Proinflammatory cytokine receptor multimeric molecules useful in thepresent invention comprise all or one or more functional portions of theLCD of two or more cytokine receptors linked via one or more polypeptidelinkers or other nonpeptide linkers. Examples of multimeric moleculesand methods for their production have been described in U.S. Pub. App.20040009149.

A preferred embodiment of the present invention is a compositioncomprising a TNF immunoreceptor fusion molecule. Such fusion moleculecomprises at least one portion of one or more immunoglobulin moleculesand all or a functional portion of one or more TNF receptors.Immunoreceptor fusion molecules can be assembled as monomers, or hetero-or homo-multimers. The immunoreceptor fusion molecules can also bemonovalent or multivalent. An example of such a TNF immunoreceptorfusion molecule is a TNF receptor/IgG fusion protein. TNF immunoreceptorfusion molecules and methods for their production have been described inthe art (Lesslauer et al. Eur. Immunol. 21:2883-2886 (1991); Ashkenaziet al. Proc. Natl. Acad. Sci. USA 88:10535-10539 (1991); Peppel et al.J. Exp. Med. 174:1481-1489 (1991); Kolls et al. Proc. Natl. Acad. Sci.USA 91:215-219 (1994); Butler et al. Cytokine 6(6):616-623 (1994); Bakeret al. Eur. J. Immunol. 24:2040-2048 (1994); and U.S. Pat. No.5,447,851. Methods for producing immunoreceptor fusion molecules canalso be found in e.g. U.S. Pat. No. 5,116,964; U.S. Pat. No. 5,225,538;and Capon et al. Nature 337:525-531 (1989).

As used herein, a “functional equivalent”, “derivative”, “fragment” or“regions” of a proinflammatory cytokine or its receptor, including thecytokine receptor molecules, refers to the portion of the cytokinereceptor molecule, or the portion or the cytokine receptor moleculesequences that encodes the cytokine receptor molecule, that is ofsufficient size and sequences to functionally resemble the cytokinereceptor molecules that can be used in the present invention as notedherein. Functional equivalents of IL-8, IL-6, IL-1, and TNF receptormolecules also include modified cytokine receptor molecules thatfunctionally resemble cytokine receptor molecules that can be used inthe present invention (e.g., bind the cytokine with high affinity andpossess low immunogenicity). A nonlimiting example includes a functionalequivalent of TNF receptor molecule can contain a silent codon, or oneor more conservative amino acid substitutions, deletions or additions(e.g., substitution of one acidic amino acid for another acidic aminoacid; or substitution of one codon encoding the same or differenthydrophobic amino acid for another codon encoding a hydrophobic aminoacid). See Ausubel et al. Current Protocols in Molecular Biology, GreenePublishing Assoc. and Wiley-Interscience, New York (1987-2000).

In one embodiment, the pharmaceutical composition is in a solution,i.e., liquid form. In one embodiment, the solutions are comprised of aproinflammatory cytokine inhibitor and amounts of a divalent cation. Theinvention also contemplates use of these solutions for the treatment ofrhinosinusitis where the biological activity of the proinflammatorycytokine inhibitor can be exploited in a novel way. The currentinvention is also directed to methods for the use of such solutions inthe preparation of further formulations comprising a proinflammatorycytokine inhibitor such as subjecting said solutions to elevatedtemperatures, e.g. as in spray-drying techniques to producepharmaceutically acceptable formulations of a proinflammatory cytokineinhibitor in the form of a respirable proinflammatory cytokineinhibitor-containing powder, suspension or solution that istherapeutically effective when administered into the upper airways elanindividual. Further, acidic solutions that inhibit deamidation of theproinflammatory cytokine inhibitor are rendered stable to precipitationwhen stored at temperatures at or about ambient temperature.

In another embodiment, the composition comprises of a liquid solutionsof proinflammatory cytokine inhibitor, where the proinflammatorycytokine inhibitor is essentially in monomeric form. Such a liquidcomposition may further comprise a divalent cation.

The source of divalent cation can be virtually any calcium salt supplieddirectly or formed in situ from a suitable pharmaceutically acceptablesource. Nonlimiting examples of alternative divalent cations can alsoinclude calcium, magnesium, zinc, and the like.

The divalent cation component of the present liquid composition isgenerally at a concentration of from about 0.01 mM to about 1 M, andmore preferably, from about 1 mM to about 50 mM.

The composition can also include agents such as an excipient, a buffer,an isotonicity agent, a preservative, a surfactant, and, a divalentcation, preferably, zinc. The composition can also include an excipientor agent for stabilization of bioactive agents, such as a buffer, areducing agent, a bulk peptide, or amino acid such as e.g., glycine orproline, or a carbohydrate. Bulk proteins useful in formulating at leastone proinflammatory cytokine inhibitor composition proteins includealbumin. Typical carbohydrates useful in formulating at least oneproinflammatory cytokine inhibitor include but are not limited tosucrose, mannitol, lactose, trehalose, or glucose.

The composition herein may contain other components, such as activeagents and inactive agents such as excipients, with the onlyrequirements being that such other components are pharmaceuticallyacceptable and do not interfere with the effect of the proinflammatorycytokine inhibitor, divalent cation or other active and inactiveingredients.

A liquid composition herein can be used as such with a delivery device,or they can be used for the preparation of pharmaceutically acceptableformulations comprising a proinflammatory cytokine inhibitor that areprepared for example by the method of spray drying. The methods of sprayfreeze-drying proteins for pharmaceutical administration of U.S. Pat.No. 6,284,282 are incorporated herein. In another embodiment of thecurrent invention, the liquid solutions herein are freeze spray driedand the spray-dried product is collected as a dispersibleproinflammatory cytokine inhibitor-containing powder that istherapeutically effective when administered into the upper airways of anindividual.

The composition is preferably administered to the mammal in apharmaceutically acceptable carrier. Suitable carriers and theirformulations are described in Remington's Pharmaceutical Sciences, 2005,Mack Publishing Co. Typically, an appropriate amount of apharmaceutically-acceptable salt is used in the formulation to renderthe formulation isotonic. Examples of the pharmaceutically acceptablecarrier include liquids such as saline, Ringer's solution, and dextrosesolution. The pH of the solution is preferably from about 5 to about 8,and more preferably from about 7 to about 7.5. The formulation may alsocomprise a lyophilized powder. Further carriers include sustainedrelease preparations such as semipermeable matrices of solid hydrophobicpolymers, which matrices are in the form of shaped articles, e.g.,films, liposomes, or microparticles. It will be apparent to thosepersons skilled in the art that certain carriers may be more preferabledepending upon, for instance, the route of administration andconcentration of proinflammatory cytokine inhibitor being administered.

Effective dosages and schedules for administering the composition may bedetermined empirically, and making such determinations is within theskill in the art. Those skilled in the art will understand that thedosage of any composition that must be administered will vary dependingon, for example, the mammal which will receive the composition, theroute of administration, the particular composition used including theco-administration of other drugs and other drugs being administered tothe mammal. A typical daily dosage of the composition used alone mightrange from about 0.25 mug to up to 5.0 mg per nasal passage, or 0.125 mgto 2.5 mg per sinus, however depending on symptoms and body weight athigher or lower dosage may be appropriate.

Alternatively, the dosage administered can vary depending upon knownfactors, such as the pharmacodynamic characteristics of the particularagent, and its mode and route of administration; age, and health of therecipient; nature and extent of symptoms, kind of concurrent treatment,frequency of treatment, and the effect desired.

As an example, treatment of mammals can be provided as a one-time orperiodic dosage of at least one antibody of the present invention 0.01to 100 mg, such as 0.025, 0.05, 0.075, 0.1, 0.125, 0.25, 0.50, 0.75,1.0, 1.125, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45,50, 60, 70, 80, 90 or 100 mg, per day, on at least one of day 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or40, or alternatively or additionally, at least one of week 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 13, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52, or alternatively oradditionally, at least one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, or 20 years, or any combination thereof, usingsingle, infusion or repeated doses. A therapeutically effective amountof a particular composition can be ratified by those of ordinary skillin the art with due consideration of the factors pertinent to thesubject.

In one embodiment, a proinflammatory cytokine inhibitor may beadministered along with other active or pharmacologic agents, such ase.g., UTP, amiloride, antibiotics, macrolides (such as e.g., tacrolimus(Rapamune)), ketolides, anti-histamines, anti-cholinergics, nasaldilators, anti-inflammatory agents, and mucolytics (e.g.,n-acetyl-cysteine). It should be understood that these other bioactiveagents may be administered without a proinflammatory cytokine inhibitorin certain cases. It may also be useful to administer theproinflammatory cytokine inhibitor along with other therapeutic humanproteins including but not limited to serine and other proteaseinhibitors, gamma-interferon, enkephalinase, nucleases, colonystimulating factors, albumin and antibodies. Still other compounds maybe used in a particular composition such as a surfactant andpreservative. The proinflammatory cytokine inhibitor may be administeredsequentially or concurrently with the one or more other pharmacologicagents. The amounts of proinflammatory cytokine inhibitor andpharmacologic agent depend, for example, on what type of drugs are used,the subtype of rhinosinusitis being treated, and the scheduling androutes of administration.

Following administration of a bioactive agent including aproinflammatory cytokine inhibitor to a mammal, the mammal'sphysiological condition can be monitored in various ways well known toone of ordinary skill in the art.

The present invention further provides compositions for the treatment,prophylaxis, and amelioration of a disorder in a subject. In oneembodiment, a composition comprises one, two, three, four or morecompounds of the invention, or a pharmaceutically acceptable salt,solvate, or hydrate thereof. In another embodiment, a compositioncomprises compounds of the invention in the form of a solution that maycontain a stabilizing compound(s) and/or a preservative(s). In anotherembodiment of the invention, bulk-drug compositions (which can benon-sterile) useful in the manufacture of pharmaceutical compositionsand in the preparation of unit dosage forms are included.

As used herein, the phrase “pharmaceutically acceptable salt” refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Preferred salts include, but are not limited, to calcium,magnesium, zinc, sulfate, citrate, acetate, oxalate, chloride, bromide,iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,lactate, salicylate, acid citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate, and pamoate (i.e., 1,1′-methylenebis(2-hydroxy-3-naphthoate)) salts. A pharmaceutically acceptable saltmay involve the inclusion of another molecule such as an acetate ion, asuccinate ion or other counterion. The counterion may be any organic orinorganic moiety that stabilizes the charge on the parent compound.Furthermore, a pharmaceutically acceptable salt may have more than onecharged atom in its structure. Instances where multiple charged atomsare part of the pharmaceutically acceptable salt can have multiplecounterions. Hence, a pharmaceutically acceptable salt can have one ormore charged atoms and/or one or more counterion.

As used herein, the term “pharmaceutically acceptable solvate” refers toan association of one or more solvent molecules and a compound of theinvention. Examples of solvents that form pharmaceutically acceptablesolvates include, but are not limited to water, saline, water-saltmixtures, isopropanol, ethanol, methanol, DMSO, ethyl acetate, aceticacid, polyethylene glycol and ethanolamine.

In one embodiment, a composition of the invention is a pharmaceuticalcomposition or a single unit dosage form. Pharmaceutical compositionsand single unit dosage forms of the invention comprise aprophylactically or therapeutically effective amount of one or morecompositions (e.g., a compound of the invention, or other prophylacticor therapeutic agent), and a typically one or more vehicles, carriers,or excipients. Preferably, the vehicles, carriers, or excipients arepharmaceutically acceptable. The term “pharmaceutically acceptable”means approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans.

In another embodiment, a composition of the invention is apharmaceutical composition or multiunit dosage form. Pharmaceuticalcompositions and multi unit dosage forms of the invention comprise aprophylactically or therapeutically effective amount of one or morecompounds (e.g., a compound of the invention, or other prophylactic ortherapeutic agent), and typically one or more vehicles, carriers, orexcipients, stabilizing agents, and/or preservatives. Preferably, thevehicles, carriers, excipients, stabilizing agents and preservatives arepharmaceutically acceptable. The term “pharmaceutically acceptable”means approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans. This invention further encompasses anhydrous pharmaceuticalcompositions and dosage forms. Anhydrous pharmaceutical compositions anddosage forms of the invention can be prepared using anhydrous or lowmoisture containing ingredients and low moisture or low humidityconditions. Pharmaceutical compositions and dosage forms that compriselactose and at least one active ingredient that comprises a primary orsecondary amine are preferably anhydrous if substantial contact withmoisture and/or humidity during manufacturing, packaging, and/or storageis expected. An anhydrous pharmaceutical composition should be preparedand stored such that its anhydrous nature is maintained. Accordingly,anhydrous compositions are preferably packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

The term “vehicle” refers to a dilutent, adjuvant, excipient, carrier,or filler with which the compound or composition of the invention isstored, transported, and/or administered. Suitable vehicles are wellknown to those skilled in the art of pharmacy, and non-limiting examplesof suitable vehicles include glucose, sucrose, peptides (such as e.g.,glycine and praline), starch, lactose, gelatin, rice, silica gel,glycerol, talc, sodium chloride, dried skim milk, propylene glycol,water, sodium stearate, ethanol, and similar substances well known inthe art. Saline solutions and aqueous dextrose and glycerol solutionscan also be employed as liquid vehicles. Whether a particular vehicle issuitable for incorporation into a pharmaceutical composition or dosageforts depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient and the specific active ingredients in thedosage form. Pharmaceutical vehicles can be sterile liquids, such aswater and oils, including those of petroleum, animal, vegetable orsynthetic origin, such as peanut oil, soybean oil, mineral oil, sesameoil and the like.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decay or the composition will change incharacter. So called “stabilizers” or “preservatives” and may include,but are not limited to, antioxidants, pH buffers, or salt buffers.Nonlimiting examples of antioxidants include butylated hydroxy anisole(BHA), ascorbic acid and derivatives thereof, tocopherol and derivativesthereof, butylated hydroxy anisole and cysteine. Nonlimiting examples ofpreservatives include parabens, such as methyl or propylp-hydroxybenzoate and benzalkonium chloride.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration within the upper airways include, but are not limitedto, nasal (e.g., inhalation or deposited expressly within the upperairway), transdermal (topical) either via nasal spray or microcatheter,or transmucosal. In various embodiments, the pharmaceutical compositionsor single unit dosage forms are sterile and in suitable form foradministration to a subject, preferably an animal subject, morepreferably a mammalian subject, and most preferably a human subject.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. Exemplary dosage forms includepowders; creams; solutions; aerosols (e.g., nasal sprays, metered ornonmetered dose atomizers, or nasal inhalers including metered doseinhalers (MDI)); gels; and liquid dosage forms suitable for mucosaladministration to a patient, including suspensions (e.g., aqueous ornon-aqueous liquid suspensions, oil-in-water emulsions, or awater-in-oil liquid emulsions), solutions, and sterile solids (e.g.,crystalline or amorphous solids) that can be reconstituted to provideliquid dosage forms suitable for upper airways administration.Formulations in the form of powders or granulates may be prepared usingthe ingredients mentioned above in a conventional manner using, e.g., amixer, a fluid bed apparatus or a spray drying equipment.

Generally, a dosage form used in the acute treatment of a disorder maycontain larger amounts of one or more of the active ingredients itcomprises than a dosage form used in the chronic treatment of the samedisease. In addition, the prophylactically and therapeutically effectivedosage form may vary among different types of disorders. For example, atherapeutically effective dosage form may contain a compound that has anappropriate antibacterial action when intending to treat an upper airwaydisorder associated with a bacterial infection. These and other ways inwhich specific dosage forms encompassed by this invention will vary fromone another and will be readily apparent to those skilled in the art.See, e.g., Remington's Pharmaceutical Sciences, Gennaro et al. 19th Ed.,Easton, Pa., Mack Publishing Co., (2005); Remington: The Science andPractice of Pharmacy; Pharmaceutical Dosage Forms and Drug DeliverySystems by Ansel et al. Lippincott Williams & Wilkins; 7th ed. (1999);and Encyclopedia of Pharmaceutical Technology, edited by Swarbrick etal. (1988), which are incorporated herein by reference in theirentirety.

The invention also provides that a pharmaceutical composition can bepackaged in a hermetically sealed container such as an ampoule orsachette indicating the quantity. In one embodiment, the pharmaceuticalcomposition can be supplied as a dry sterilized lyophilized powder in adelivery device suitable for administration to the upper airways of apatient. The pharmaceutical compositions can, if desired, be presentedin a pack or dispenser device that can contain one or more unit dosageforms containing the active ingredient. The pack can for examplecomprise metal or plastic foil, such as a blister pack. The pack ordispenser device can be accompanied by instructions for administration.

Depending on the manner of use, the compositions or compounds of theinvention can be co-administered with another modality, or thecompositions or compounds of the invention can be mixed and thenadministered as a single composition to a subject.

In one embodiment, one or more compound(s) of the invention or acomposition of the invention can be added to an over-the-counter,non-prescription medication. Examples of such medication include but arenot limited to an analgesic, acetaminophen, non-steroidalanti-inflammatory agent, salicylate, antibiotic, antihistamine,antipruritics, antipyretics, decongestant, expectorant, steroid, zincand wound care products.

Therapeutic or prophylactic agents include, but are not limited to,plant extracts, small molecules, synthetic drugs, peptides,polypeptides, proteins, nucleic acids (e.g., DNA and RNA nucleotidesincluding, but not limited to, antisense nucleotide sequences, RNAi,triple helices and nucleotide sequences encoding biologically activeproteins, polypeptides or peptides), antibodies, synthetic or naturalinorganic molecules, mimetic agents, and synthetic or natural organicmolecules. In a specific embodiment, the composition comprises one, two,three, four or more compounds of the invention, or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof; and one, two, three, fouror more immunomodulatory agents. In another embodiment, the compositioncomprises one, two, three, four or more compounds of the invention, or apharmaceutically acceptable salt, solvate, or hydrate thereof; and one,two, three, four or more anti-angiogenic agents. In yet anotherembodiment, the composition comprises one, two, three, four or morecompounds of the invention, or a pharmaceutically acceptable salt,solvate, or hydrate thereof, and one, two, three, four or moreanti-inflammatory agents. In another embodiment, the compositioncomprises one, two, three, four or more compounds of the invention, or apharmaceutically acceptable salt, solvate hydrate thereof, and one, two,three, four or more anti-cancer agents. In another embodiment, thecomposition comprises one, two, three, four or more compounds of theinvention, or a pharmaceutically acceptable salt, solvate, or hydratethereof, and one, two, three, four or more anti-viral agents. In anotherembodiment, a composition comprises one, two, three, four or morecompounds of the invention, or a pharmaceutically acceptable salt,solvate, or hydrate thereof, and one, two, three, four or more one ormore antibiotics. In another embodiment, a composition comprising one,two, three, four or more compounds of the invention, or apharmaceutically acceptable salt, solvate, or hydrate thereof, or one ormore natural products, phytochemicals, or botanical extracts. In yetanother embodiment, a composition comprises one, two, three, four ormore compounds of the invention, or a pharmaceutically acceptable salt,solvate, or hydrate thereof, and any combination of one, two, three, ormore of each of the following prophylactic or therapeutic agents: animmunomodulatory agent, an anti-angiogenic agent, a botanical extract,an immunomodulatory agent, an anti-inflammatory agent, an anti-viralagent, or an anti-bacterial agent (e.g., an antibiotic).

Any agent which contributes to the prevention, management, treatment, oramelioration of a disorder (e.g., rhinosinusitis) or one or moresymptoms thereof can be used as a compound of the invention inaccordance with the invention described herein. See, e.g., Gilman et al.Goodman and Gilman's: The Pharmacological Basis of Therapeutics, TenthEd., McGraw-Hill, New York, 2001; The Merck Manual of Diagnosis andTherapy, Berkow et al. (eds.) Cecil Textbook of Medicine, 20th Ed.,Bennett and Plum (eds.), W.B. Saunders, for information regardingprophylactic or therapeutic agents which have been or are currentlybeing used for preventing, treating, managing, or amelioratingproliferative disorders or inflammatory disorders or one or moresymptoms thereof. Nonlimiting examples of such agents includeanti-inflammatory agents such as corticosteroids prednisone andhydrocortisone), glucocorticoids, steroids, non-steroidalanti-inflammatory drugs (e.g., aspirin, ibuprofen, diclofenac, COX-1and/or COX-2 inhibitors), beta-agonists, anticholinergic agents,mucoregulators (e.g., niflumic acid, talniflumate, MSI-2216) and methylxanthines), immunomodulatory agents, sulphasalazine, penicillamine,anti-angiogenic agents (e.g., angiostatin), anti-fibrotics, opioids(e.g., morphine, heroin, hydromorphone, hydrocodone, oxymorphone,oxycodone, metopon, apomorphine, normorphine, etorphine, buprenorphine,meperidine, lopermide, anileridine, ethoheptazine, piminidine,betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil,remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine,cyclazocine, methadone, isomethadone and propoxyphene), hematopoieticcolony stimulating factors (e.g., filgrastim, pegfilgrastimsargramostim, molgramostim and epoetin alfa), antihistamines, anti-viralagents, antibiotics (e.g., dactinomycin (formerly actinomycin),bleomycin, erythromycin, penicillin, mithramycin, and anthramycin(AMC)), macrolide antibiotics (e.g., erythromycin, azithromycin(Zithromax, Zitromax), clarithromycin (Biaxin), dirithromycin (Dynabac),roxithromycin (Rulid, Surlid), carbomycin A, josamycin, kitasamycin,oleandomycin, spiramycin, troleandomycin, tylosin/tylocine (Tylan),midecamicine/midecamicine acetat), ketolides (e.g., telithromycin(Ketek), cethromycin, spiramycin, ansamycin, oleandomycin, carbomycinand tylocine), non-antibiotic macrolides (e.g., tacrolimus (Rapamune)and cyclosporin).

Anti-Angiogenic Agents

The composition comprising a proinflammatory cytokine inhibitor mayfurther contain an anti-angiogenic agent. Suitable anti-angiogenicagents include proteins, polypeptides, peptides, fusion proteins,antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal,Fvs, ScFvs, Fab fragments, F(ab)2 fragments, and antigen-bindingfragments thereof) such as antibodies that immunospecifically bind toTNF-alpha, nucleic acid molecules (e.g., antisense molecules or triplehelices), organic molecules, inorganic molecules, and small moleculesthat reduce or inhibit angiogenesis. In particular, examples ofanti-angiogenic agents, include, but are not limited to, squalamine,endostatin, angiostatin, apomigren, anti-angiogenic antithrombin III,the 29 kDa N-terminal and a 40 kDa C-terminal proteolytic fragments offibronectin, a uPA receptor antagonist, the 16 kDa proteolytic fragmentof prolactin, the 7.8 kDa proteolytic fragment of platelet factor-4, theanti-angiogenic 24 amino acid fragment of platelet factor-4, theanti-angiogenic factor designated 13.40, the anti-angiogenic 22 aminoacid peptide fragment of thrombospondin I, the anti-angiogenic 20 aminoacid peptide fragment of SPARC, ROD and NGR containing peptides, thesmall anti-angiogenic peptides of laminin, fibronectin, procollagen andEGF, anti-integrin alpha V beta 3 antibodies, acid fibroblast growthfactor (aFGF) antagonists, basic fibroblast growth factor (bFGF)antagonists, vascular endothelial growth factor (VEGF) antagonists(e.g., anti-VEGF antibodies such as AVASTIN, and VEGF receptor (VEGFR)antagonists (e.g., anti-VEGFR antibodies)).

Examples of integrin alpha V beta 3 antagonists include, but are notlimited to, proteinaceous agents such as non-catalytic metalloproteinasefragments, ROD peptides, peptide mimetics, fusion proteins, disintegrinsor derivatives or analogs thereof, and antibodies thatimmunospecifically bind to integrin alpha V beta 3, nucleic acidmolecules, organic molecules, and inorganic molecules. Non-limitingexamples of antibodies that immunospecifically bind to integrin alpha Vbeta 3 include 11D2 (Searle). Non-limiting examples of small moleculepeptidometric integrin alpha V beta 3 antagonists include S836 (Searle)and S448 (Searle). Examples or disintegrins include, but are not limitedto, Accutin. The invention also encompasses the use of any of theintegrin alpha V beta 3 antagonists disclosed in the following U.S.Patents and International publications in the compositions and methodsof the invention: U.S. Pat. Nos. 5,652.109; 5,652,110; 5,578,704;5,149,780; 5,196,511; 5,204,445; 5,262,520; 5,306,620; 5,478,725;5,498,694; 5,523,209; 5,578,704; 5,589,570; 5,652,109; 5,652,110;5,693,612; 5,705,481; 5,753,230; 5,767,071; 5,770,565; 5,780,426;5,817,457; 5,830,678; 5,849,692; 5,955,572; 5,985,278; 6,043,861;6,090,944; 6,096,707; 6,130,231; 6,153,628; 6,160,099; and 6,171,58; andInternational Publication WO 95/22543; WO 98/133919; WO 00/78815; WO00/31248; WO 98/46264; WO 98/40488; and WO 02/070007.

In one embodiment, the anti-angiogenic agent is the anti-angiogenic formof antithrombin. In another embodiment of the invention, theanti-angiogenic agent is the 40 kD and/or 29 kDa proteolytic fragment offibronectin.

Nucleic acid molecules encoding proteins, polypeptides, or peptides withanti-angiogenic activity, or proteins, polypeptides or peptides withanti-angiogenic activity can be administered to a subject with adisorder (e.g., a disorder characterized by or associated with aberrantangiogenesis, a proliferative disorder, an inflammatory disorder or adisorder prevented, managed, treated or ameliorated by inhibitingNF-kappa B activation and phosphorylation of p44/42 MAPK, or by reducingor inhibiting production of NO, IL-1 beta, and expression of iNOS andCox-2 gene expression) in accordance with the methods of the invention.Further, nucleic acid molecules encoding derivatives, analogs,fragments, or variants of proteins, polypeptides, or peptides withanti-angiogenic activity, or derivatives, analogs, fragments, orvariants of proteins, polypeptides, or peptides with anti-angiogenicactivity can be administered to a subject with a disorder (e.g., adisorder characterized by or associated with aberrant angiogenesis, aproliferative disorder, an inflammatory disorder or a disorderprevented, managed, treated or ameliorated by inhibiting NF-kappa Bactivation and phosphorylation of p44/42 MAPK, or by reducing orinhibiting production of NO, IL-1 beta, and expression of iNOS and Cox-2gene expression) in accordance with the methods of the invention.Preferably, such derivatives, analogs, variants, and fragments retainthe anti-angiogenic activity of the full-length, wild-type protein,polypeptide, or peptide.

Proteins, polypeptides, or peptides that can be used as anti-angiogenicagents an be produced by any technique well known in the art ordescribed herein. Proteins, polypeptides or peptides withanti-angiogenic activity can be engineered so as to increase the in vivohalf-life of such proteins, polypeptides, or peptides utilizingtechniques well known in the art or described herein. Preferably,anti-angiogenic agents that are commercially available are used in thecompositions and methods of the invention. The anti-angiogenic activityof an agent can be determined in vitro and/or in vivo by any techniquewell known to one skilled in the art or described herein.Anti-angiogenic agents and their dosages, routes of administration andrecommended usage are known in the art and have been described in suchliterature as the Physician's Desk Reference (60th ed., 2006).

Anti-Inflammatory Agents

In one embodiment of the invention, the composition further comprises ananti-inflammatory agent. Thus, anti-inflammatory therapy (e.g., ananti-inflammatory agent) can be used in the compositions and methods ofthe invention. Non-limiting examples of suitable anti-inflammatoryagents include non-steroidal anti-inflammatory drugs (NSAIDs), steroidalanti-inflammatory drugs, beta-agonists, anticholinergic agents,antihistamines (e.g., ethanolamines, ethylenediamines, piperazines, andphenothiazine), and methyl xanthines. Examples of NSAIDs include, butare not limited to, aspirin, ibuprofen, salicylate, acetaminophen,celecoxib (CELEBREX), diclofenac (VOLTAREN), etodolac (LODINE),fenoprofen (NALFON), indomethacin (INDOCIN), ketoralac (TORADOL),oxaprozin (DAYPRO), nabumentone (RELAFEN), sulindac (CLINORIL),tolmentin (TOLECTIN), rofecoxib (VIOXX), naproxen (ALEVE, NAPROSYN),ketoprofen (ACTRON), nabumetone (RELAFEN), macrolide antibiotics (e.g.,erythromycin, azithromycin (Zithromax, Zitromax), clarithromycin(Biaxin), dirithromycin (Dynabac), roxithromycin (Rulid, Surlid),carbomycin A, josamycin, kitasamycin, oleandomycin, spiramycin,troleandomycin, tylosin/tylocine (Tylan), midecamicine/midecamicineacetat), ketolides (e.g., telithromycin (Ketek), cethromycin Others are:spiramycin (used for treating toxoplasmosis), ansamycin, oleandomycin,carbomycin and tylocine), non-antibiotic macrolides (e.g., tacrolimus(Rapamune), and cyclosporin. Such NSAIDs function by inhibiting acyclooxgenase enzyme (e.g., COX-1 and/or COX-2). Examples of steroidalanti-inflammatory drugs include, but are not limited to,glucocorticoids, dexamethasone (DECADRON), cortisone, hydrocortisone,prednisone (DELTASONE), prednisolone, triamcinolone, azulfidine, andeicosanoids such as prostaglandins, thromboxanes, and leukotrienes.Anti-inflammatory agents and their dosages, routes of administration andrecommended usage are known in the art and have been described in suchliterature as the Physician's Desk Reference (60^(th) ed., 2006),

Antibiotics

The composition may also further comprise an antibacterial agent and/orantibiotic. Suitable antibacterial agent and/or antibiotic include butare not limited to: aminoglycoside antibiotics (e.g., apramycin,arbekacin, bambermycins, butirosin, dibekacin, neomycin, neomycin,undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin, andspectinomycin), amphenicol antibiotics (e.g., azidamfenicol,chloramphenicol, florfenicol, and thiamphenicol), ansamycin antibiotics(e.g., rifamide and rifampin), carbacephems (e.g., loracarbef),carbapenems (e.g., biapenem and imipenem), cephalosporins (e.g.,cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefozopran,cefpimizole, cefpiramide, and cefpirome), cephamycins (e.g.,cefbuperazone, cefmetazole, and cefminox), monobactams (e.g., aztreonam,carumonam, and tigemonam), oxacephems (e.g., flomoxef, and moxalactam),penicillins (e.g., amdinocillin, amdinocillin pivoxil, amoxicillin,bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium,epicillin, fenbenicillin, floxacillin, penamccillin, penethamatehydriodide, penicillin o-benethamine, penicillin 0, penicillin V,penicillin V benzathine, penicillin V hydrabamine, penimepicycline, andphencihicillin potassium), lincosamides (e.g., clindamycin, andlincomycin), macrolides (e.g., azithromycin, carbomycin, clarithomycin,dirithromycin, erythromycin, and erythromycin acistrate), amphomycin,bacitracin, capreomycin, colistin, enduracidin, enviomycin,tetracyclines (e.g., apicycline, chlortetracycline, clomocycline, anddemeclocycline), 2,4-diaminopyrimidines (e.g., brodimoprim), nitrofurans(e.g., furaltadone, and furazolium chloride), quinolones and analogsthereof (e.g., cinoxacin, ciprofloxacin, clinafloxacin, flumequine, andgrepagloxacin), sulfonamides (e.g., acetyl sulfamethoxypyrazine,benzylsulfamide, noprylsulfamide, phthalylsulfacetamide,sulfachrysoidine, and sulfacytine), sulfones (e.g., diathymosulfone,glucosulfone sodium, and solasulfone), cycloserine, mupirocin andtuberin.

Additional nonlimiting examples of antibacterial agents includeAcedapsone; Acetosulfone Sodium; Alamecin; Alexidine; Amdinocillin;Amdinocillin Pivoxil; Amicycline; Amifloxacin; Amifloxacin Mesylate;Amikacin; Amikacin Sulfate; Aminosalicylic acid; Aminosalicylate sodium;Amoxicillin; Amphomycin; Ampicillin; Ampicillin Sodium; ApalcillinSodium; Apramycin; Aspartocin; Astromicin Sulfate; Avilamycin;Avoparcin; Azithromycin; Azlocillin; Azlocillin Sodium; BacampicillinHydrochloride; Bacitracin; Bacitracin Methylene Disalicylate; BacitracinZinc; Bambermycins; Benzoylpas Calcium; Berythromycin; BetamicinSulfate; Biapenem; Biniramycin; Biphenamine Hydrochloride; BispyrithioneMagsulfex; Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carbadox;Carbenicillin Disodium; Carbenicillin Indanyl Sodium; CarbenicillinPhenyl Sodium; Carbenicillin Potassium; Carumonam Sodium; Cefaclor;Cefadroxil; Cefamandole; Cefamandole Nafate; Cefamandole Sodium;Cefaparole; Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium;Cefbuperazone; Cefdinir; Cefepime; Cefepime Hydrochloride; Cefetecol;Cefixime; Cefmnenoxime Hydrochloride; Cefmetazole; Cefmetazole Sodium;Cefonicid Monosodium; Cefonicid Sodium; Cefoperazone Sodium; Ceforanide;Cefotaxime Sodium; Cefotetan; Cefotetan Disodium; CefotiamHydrochloride; Cefoxitin; Cefoxitin Sodium; Cefpimizole; CefpimizoleSodium; Cefpiramide; Cefpiramide Sodium; Cefpirome Sulfate; CefpodoximeProxetil; Cefprozil; Cefroxadine; Cefsulodin Sodium; Ceftazidime;Ceftibuten; Ceftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime;Cefuroxime Axetil; Cefuroxime Pivoxetil; Cefuroxime Sodium; CephacetrileSodium; Cephalexin; Cephalexin Hydrochloride; Cephaloglycin;Cephaloridine; Cephalothin Sodium; Cephapirin Sodium; Cephradine;Cetocycline Hydrochloride; Cetophenicol; Chloramphenicol;Chloramphenicol Palmitate; Chloramphenicol Pantothenate Complex;Chloramphenicol Sodium Succinate; Chlorhexidine Phosphanilate;Chloroxylenol; Chlortetracycline Bisulfate; ChlortetracyclineHydrochloride; Cinoxacin; Ciprofloxacin; Ciprofloxacin Hydrochloride;Cirolemycin; Clarithromycin; Clinafloxacin Hydrochloride; Clindamycin;Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride;Clindamycin Phosphate; Clofazimine; Cloxacillin Benzathine; CloxacillinSodium; Cloxyquin; Colistimethate Sodium; Colistin Sulfate; Coumermycin;Coumermycin Sodium; Cyclacillin; Cycloserine; Dalfopristin; Dapsone;Daptomycin; Demeclocycline; Demeclocycline Hydrochloride; Demecycline;Denofungin; Diaveridine; Dicloxacillin; Dicloxacillin Sodium;Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin; Doxycycline;Doxycycline Calcium; Doxycycline Fosfatex; Doxycycline Hyclate; DroxacinSodium; Enoxacin; Epicillin; Epitetracycline Hydrochloride;Erythromycin; Erythromycin Acistrate; Erythromycin Estolate;Erythromycin Ethylsuccinate; Erythromycin Gluceptate; ErythromycinLactobionate; Erythromycin Propionate; Erythromycin Stearate; EthambutolHydrochloride; Ethionamide; Fleroxacin; Floxacillin; Fludalanine;Flumequine; Fosfomycin; Fosfomycin Tromethamine; Fumoxicillin;Furazolium Chloride; Furazolium Tartrate; Fusidate Sodium; Fusidic Acid;Gentamicin Sulfate; Gloximonam; Gramicidin; Haloprogin; Hetacillin;Hetacillin Potassium; Hexedine; Ibafloxacin; Imipenem; Isoconazole;Isepamicin; Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin;Levofuraltadone; Levopropylcillin Potassium; Lexithromycin; Lincomycin;Lincomycin Hydrochloride; Lomefloxacin; Lomefloxacin Hydrochloride;Lomefloxacin Mesylate; Loracarbef; Mafenide; Meclocycline; MeclocyclineSulfosalicylate; Megalomicin Potassium Phosphate; Mequidox; Meropenem;Methacycline; Methacycline Hydrochloride; Methenamine; MethenamineHippurate; Methenamine Mandelate; Methicillin Sodium; Metioprim;Metronidazole Hydrochloride; Metronidazole Phosphate; Mezlocillin;Mezlocillin Sodium; Minocycline; Minocycline Hydrochloride; MirincamycinHydrochloride; Monensin; Monensin Sodium; Nafcillin Sodium; NalidixateSodium; Nalidixic Acid; Natamycin; Nebramycin; Neomycin Palmitate;Neomycin Sulfate; Neomycin Undecylenate; Netilmicin Sulfate;Neutramycin; Nifuradene; Nifuraldezone; Nifuratel; Nifuratrone;Nifurdazil; Nifurimide; Nifurpirinol; Nifurquinazol; Nifurthiazole;Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin; Novobiocin Sodium;Ofloxacin; Gatifloxacin Ormetoprim; Oxacillin Sodium; Oximonam; OximonamSodium; Oxolinic Acid; Oxytetracycline; Oxytetracycline Calcium;Oxytetracycline Hydrochloride; Paldimycin; Parachlorophenol; Paulomycin;Pefloxacin; Pefloxacin Mesylate; Penamecillin; Penicillin G Benzathine;Penicillin G Potassium; Penicillin G Procaine; Penicillin G Sodium;Penicillin V; Penicillin V Benzathine; Penicillin V Hydrabamine;Penicillin V Potassium; Pentizidone Sodium; Phenyl Aminosalicylate;Piperacillin Sodium; Pirbenicillin Sodium; Piridicillin Sodium;Pirlimycin Hydrochloride; Pivampicillin Hydrochloride; PivampicillinPamoate; Pivampicillin Probenate; Polymyxin B Sulfate; Porfiromycin;Propikacin; Pyrazinamide; Pyrithione Zinc; Quindecamine Acetate;Quinupristin; Racephenicol; Ramoplanin; Ranimycin; Relomycin;Repromicin; Rifabutin; Rifametane; Rifamexil; Rifamide; Rifampin;Rifapentine; Rifaximin; Rolitetracycline; Rolitetracycline Nitrate;Rosaramicin; Rosaramicin Butyrate; Rosaramicin Propionate; RosaramicinSodium Phosphate; Rosaramicin Stearate; Rosoxacin; Roxarsone;Roxithromycin; Sancycline; Sanfetrinem Sodium; Sarmoxicillin;Sarpicillin; Scopafingin; Sisomicin; Sisomicin Sulfate; Sparfloxacin;Spectinomycin Hydrochloride; Spiramycin; Stallimycin Hydrochloride;Steffimycin; Streptomycin Sulfate; Streptonicozid; Sulfabenz;Sulfabenzamide; Sulfacetamide; Sulfacetamide Sodium; Sulfacytine;Sulfadiazine; Sulfadiazine Sodium; Sulfadoxine; Sulfalene;Sulfamerazine; Sulfameter; Sulfamethazine; Sulfamethizole;Sulfamethoxazole; Sulfamonomethoxine; Sulfamoxole; Sulfanilate Zinc;Sulfanitran; Sulfasalazine; Sulfasomizole; Sulfathiazole; Sulfazamet;Sulfisoxazole; Sulfisoxazole Acetyl; Sulfisoxazole Diolamine;Sulfomyxin; Sulopenem; Sultamicillin; Suncillin Sodium; TalampicillinHydrochloride; Teicoplanin; Temafloxacin Hydrochloride; Temocillin;Tetracycline; Tetracycline Hydrochloride; Tetracycline PhosphateComplex; Tetroxoprim; Thiamphenicol; Thiphencillin Potassium;Ticarcillin Cresyl Sodium; Ticarcillin Disodium; Ticarcillin Monosodium;Ticlatone; Tiodonium Chloride; Tobramycin; Tobramycin Sulfate;Tosufloxacin; Trimethoprim; Trimethoprim Sulfate; Trisulfapyrimidines;Troleandomycin; Trospectomycin Sulfate; Tyrothricin; Vancomycin;Vancomycin Hydrochloride; Virginiamycin; Zorbamycin, macrolideantibiotics (e.g., erythromycin, azithromycin (Zithromax, Zitromax),clarithromycin (Biaxin), dirithromycin (Dynabac), roxithromycin (Rulid,Surlid), carbomycin A, josamycin, kitasamycin, oleandomycin, spiramycin,troleandomycin, tylosin/tylocine (Tylan), midecamicine/midecamicineacetat), and ketolides antibiotics (e.g., telithromycin (Ketek),cethromycin, spiramycin ansamycin, oleandomycin, carbomycin andtylocine).

Antibiotics and their dosages, routes of administration and recommendedusage are known in the art and have been described in such literature asthe Physician's Desk Reference (60^(th) ed., 2006).

Antiviral Agents

In another embodiment, the composition may contain an anti-viral agent.Non-limiting examples of anti-viral agents include proteins,polypeptides, peptides, fusion protein antibodies, nucleic acidmolecules, organic molecules, inorganic molecules, and small moleculesthat inhibit or reduce the attachment of a virus to its receptor, theinternalization of a virus into a cell, the replication of a virus, orrelease of virus from a cell.

Many examples of antiviral compounds that can be used in combinationwith the compounds of the invention are known in the art and include butare not limited to: rifampicin, nucleoside reverse transcriptaseinhibitors (e.g., AZT, ddI, ddC, 3TC, d4T), non-nucleoside reversetranscriptase inhibitors (e.g., Efavirenz, Nevirapine), proteaseinhibitors (e.g., aprenavir, indinavir, ritonavir, and saquinavir),idoxuridine, eidofovir, acyclovir, ganciclovir, zanamivir, amantadine,and Palivizumab. Other examples of anti-viral agents include but are notlimited to Acemannan; Acyclovir; Acyclovir Sodium; Adefovir; Alovudine;Alvircept Sudotox; Amantadine Hydrochloride; Aranotin; Arildone;Atevirdine Mesylate; Avridine; Cidofovir; Cipamfylline; CytarabineHydrochloride; Delavirdine Mesylate; Desciclovir; Didanosine; Disoxaril;Edoxudine; Enviradene; Enviroxime; Famciclovir; Famotine Hydrochloride;Fiacitabine; Fialuridine; Fosarilate; Foscamet Sodium; Fosfonet Sodium;Ganciclovir; Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine;Lobucavir; Memotine Hydrochloride; Methisazone; Nevirapine; Penciclovir;Pirodavir; Ribavirin; Rimantadine Hydrochloride; Saquinavir Mesylate;Somantadine Hydrochloride; Sorivudine; Statolon; Stavudine; TiloroneHydrochloride; Trifluridine; Valacyclovir Hydrochloride; Vidarabine;Vidarabine Phosphate; Vidarabine Sodium Phosphate; Viroxime;Zalcitabine; Zidovudine; Zinviroxime, zinc, heparin, anionic polymers.Antiviral agents and their dosages, routes of administration andrecommended usage are known in the art and have been described in suchliterature as the Physician's Desk Reference (60^(th) ed., 2006).

Antifungal Compounds

In addition, the composition may further contain an antifungal compound.Exemplary antifungal compounds include but are not limited to; polyenes(e.g., amphotericin b, candicidin, mepartricin, natamycin, andnystatin), allylamines (e.g., butenafine, and naftifine), imidazoles(e.g., bifonazole, butoconazole, chlordantoin, flutrimazole,isoconazole, ketoconazole, and lanoconazole), thiocarbamates (e.g.,tolciclate, tolindate, and tolnaftate), triazoles (e.g., fluconazole,itraconazole, saperconazole, and terconazole), bromosalicylchloranilide,buclosamide, calcium propionate, chlorphenesin, ciclopirox, azaserine,griseofulvin, oligomycins, neomycin undecylenate, pyrrolnitrin,siccanin, tubercidin, and viridin. Additional examples of antifungalcompounds include but are not limited to Acrisorcin; Ambruticin;Amphotericin B; Azaconazole; Azaserine; Basifungin; Bifonazole;Biphenamine Hydrochloride; Bispyrithione Magsulfex; ButoconazoleNitrate; Calcium Undecylenate; Candicidin; Carbol-Fuchsin; Chlordantoin;Ciclopirox; Ciclopirox Olamine; Cilofungin; Cisconazole; Clotrimazole;Cuprimyxin; Denofungin; Dipyrithione; Doconazole; Econazole; EconazoleNitrate; Enilconazole; Ethonam Nitrate; Fenticonazole Nitrate; Filipin;Fluconazole; Flucytosine; Fungimycin; Griseofulvin; Hamycin;Isoconazole; Itraconazole; Kalafungin; Ketoconazole; Lomofingin;Lydimycin; Mepartricin; Miconazole; Miconazole Nitrate; Monensin;Monensin Sodium; Naftifine Hydrochloride; Neomycin Undecylenate;Nifuratel; Nifurmerone; Nitralamine Hydrochloride; Nystatin; OctanoicAcid; Orconazole Nitrate; Oxiconazole Nitrate; Oxifungin Hydrochloride;Parconazole Hydrochloride; Partricin; Potassium Iodide; Proclonol;Pyrithione Zinc; Pyrrolnitrin; Rutamycin; Sanguinarium Chloride;Saperconazole; Scopafungin; Selenium Sulfide; Sinefungin; SulconazoleNitrate; Terbinafine; Terconazole; Thiram; Ticlatone; Tioconazole;Tolciclate; Tolindate; Tolnaftate; Triacetin; Triafuigin; UndecylenicAcid; Viridoflilvin; Zinc Undecylenate; and Zinoconazole Hydrochloride.

Antifungal agents and their dosages, routes of administration andrecommended usage are known in the art and have been described in suchliterature as the Physician's Desk Reference (60^(th) ed., 2006).

Antiprotozoal Compounds

The composition may further comprise antiprotozoal compounds.Antiprotozoal compounds can be used in the methods and compositions ofthe invention to treat parasitic diseases are known in the art andinclude but are not limited to: quinines, chloroquine, mefloquine,proguanil, pyrimethamine, metronidazole, diloxanide furoate, tinidazole,amphotericin, sodium stibogluconate, trimoxazole, and pentamidineisetionate. Many examples of antiparasite drugs that can be used incombination with the compounds and compositions Of the invention totreat parasitic diseases are known in the art and include but are notlimited to: mebendazole, levamisole, niclosamide, praziquantel,albendazole, ivermectin, diethylcarbamazine, and thiabendazole. Furtherexamples of anti-parasitic compounds include but are not limited toAcedapsone; Amodiaquine Hydrochloride; Amquinate; Arteflene;Chloroquine; Chloroquine Hydrochloride; Chloroquine Phosphate;Cycloguanil Pamoate; Enpiroline Phosphate; Halofantrine Hydrochloride;Hydroxychloroquine Sulfate; Mefloquine Hydrochloride; Menoctone;Mirincamycin Hydrochloride; Primaquine Phosphate; Pyrimethamine; QuinineSulfate; and Tebuquine. Antiprotozoal agents and their dosages, routesof administration and recommended usage are known in the art and havebeen described in such literature as the Physician's Desk Reference(60^(th) ed., 2006).

Mucoregulator Compounds

In another embodiment of the invention, the composition may also containa mucoregulator. Mucoregulator compound downregulate the production ofsoluble gel-forming mucins in rhinosinusitis. These compounds andmethods of modulating mucin synthesis and the therapeutic application ofcompounds in controlling mucin over-production in rhinosinusitis aredescribed in U.S. Pat. Nos. 6,737,427; 6,576,434; 6,037,149 and5,908,839, all of which are herein incorporated by reference in itsentirety.

Molecules that decrease mucin synthesis or levels include analogues andderivatives of anthranilic acid (2-aminobenzoic acid), N-derivatizedanthranilic acid, flufenamic acid, derivatives of 2-amino-nicotinicacid, derivative of 2-amino-phenylacetic acid, talniflumate,bendroflumethiazide, or a prodrug of any of these compounds. A prodrugis a molecule that is administered in a form other than that describedabove and is converted in the body of the subject into the formdescribed herein. Preferred prodrugs include, but are not limited to,prodrugs of fenamates. Some preferred prodrugs are esters of the acidform of the molecule that decreases mucin synthesis or levels. Preferredesters include, but are not limited to, esters of NFA, for example, thebeta-morpholinoethyl ester, morniflumate, and the phthalidyl ester,talniflumate. The term “hydrating agent” or “hydrating substance” asused herein includes but is not limited to the following saline,hypertonic saline, polyethylene glycol or glycerol.

Surfactants

The pharmaceutical compositions according to the invention may furthercomprise a surfactant. One or more surfactant may be used to preventsoluble and insoluble aggregation and/or precipitation of proteinsincluded in the composition. Suitable surfactants include but are notlimited to sorbitan trioleate, soya lecithin, and oleic acid. In certaincases, solution aerosols are preferred using solvents such as ethanol.Thus, at least one proinflammatory cytokine inhibitor formulation canalso include a surfactant that can reduce or prevent surface-inducedaggregation of the inhibitor caused by atomization of the solution informing an aerosol. Various conventional surfactants can be employed,such as polyoxyethylene fatty acid esters and alcohols, andpolyoxyethylene sorbital fatty acid esters. Amounts will generally rangebetween 0.001 and 4% by weight of the formulation. Especially preferredsurfactants are polyoxyethylene sorbitan mono-oleate, polysorbate 80,polysorbate 20. Additional agents known in the art can also be includedin the composition.

Surfactants and spreading agents can be used in the compositions and themethods of the invention. Surfactants as noted above may be used toimprove delivery and/or stability of the composition, minimize heat andagitation induced soluble and insoluble aggregation of proteins, aidrehydration and/or wetting of membranes, and fluidity secretions.Non-limiting examples of surfactants include various water-soluble orinsoluble sugar esters such as TWEEN 80 (polysorbate 80); TWEEN 20, andSPAN 60 (sorbitan monostearate). Other commercial surfactants that maybe used include pulmonary surfactants such as, e.g., 1,2Dipalmitoylphosphatidylcholine;1,2-Dihexadecyl-sn-Glycerophosphocholine; 1,2 Dihexadecyl snGlycerophosphocholine; Dipalmitoylphosphatidylcholine;Dipalmitoyllecithin; Dipalmitoyl Phosphatidylcholine;Phosphatidylcholine, Dipalmitoyl Dipalmitoylglycero-phosphocholine;1,2-Dipalmitoyl-Glycerophosphocholine; 1,2 DipalmitoylGlycerophosphocholine; Exosurf, Colfoseril palmitate; polyethyleneglycol or PEG, 3-(3-hydroxyalkanoyloxy)alkanoic acids, ALKANOL 189-S,ALKANOL 6112, ALKANOL XC, MERPOL, MERPOL DA, MERPOL HCS, MERPOL LFH,MERPOL OJ, MERPOL SE, BL; polyocyalkylene block copolymers. Additionalnonionic agents include: BigCHAP; Bis(polyethylene glycol bis(imidazoylcarbonyl)), Powder; BRIJ 35, Stein-Moore chromatography; BRIJ 56; BRIJ72; BRIJ 76; BRIJ 92V; BRIJ 97; BRIJ 58P; CREMOPHOR EL; Decaethyleneglycol monododecyl ether; N-Decanoyl-N-methylglucamine; n-Decylα-D-glucopyranoside; Decyl β-D-maltopyranoside;n-Dodecanoyl-N-methylglucamide; n-Dodecyl α-D-maltoside; n-Dodecylβ-D-maltoside; n-Dodecyl β-D-maltoside; Heptaethylene glycol monodecylether; heptaethylene glycol monododecyl ether; Heptaethylene glycolmonotetradecyl ether; n-Hexadecyl β-D-maltoside; Hexaethylene glycolmonododecyl ether; Hexaethylene glycol monohexadecyl ether; Hexaethyleneglycol monooctadecyl ether; Hexaethylene glycol monotetradecyl ether;Igepal CA-630; Methyl-6-O-(N-heptylcarbamoyl)-α-D-glucopyranoside;Nonaethylene glycol monododecyl ether; N-Nonanoyl-N-methylglucamine;N-Nonanoyl-N-methylglucamine; octaethylene glycol monodecyl ether;Octaethylene glycol monododecyl ether; Octaethylene glycol monohexadecylether; Octaethylene glycol monooctadecyl ether; Octaethylene glycolmonotetradecyl ether; Octyl-β-D-glucopyranoside; Pentaethylene glycolmonodecyl ether; Pentaethylene glycol monododecyl ether; Pentaethyleneglycol monohexadecyl ether; Pentaethylene glycol monohexyl ether,Pentaethylene glycol monooctadecyl ether; Pentaethylene glycol monooctylether; Polyethylene glycol diglycidyl ether; Polyethylene glycol etherW-1; Polyoxyethylene 10 tridecyl ether; Polyoxyethylene 100 stearate;Polyoxyethylene 20 isohexadecyl ether; Polyoxyethylene 20 oleyl ether;Polyoxyethylene 40 stearate; Polyoxyethylene 50 stearate;Polyoxyethylene 8 stearate; Polyoxyethylene bis(imidazolyl carbonyl);Polyoxyethylene 25 propylene glycol stearate; Saponin from Quillajabark; SPAN 20; SPAN 40; SPAN 60; SPAN 65; SPAN 80; SPAN 85; Tergitol,Type 15-S-12; Tergitol, Type 15-S-30; Tergitol, Type 15-S-5; Tergitol,Type 15-S-7; Tergitol, Type 15-S-9; Tergitol, Type NP-10; Tergitol, TypeNP-4; Tergitol, Type NP-40; Tergitol, Type NP-7; Tergitol, Type NP-9;Tergitol, MIN FOAM 1x; Tergitol, MIN FOAM 2; Tergitol, Type TMN-10;Tergitol, Type TMN-6; Tetradecyl-β-D-maltoside; Tetraethylene glycolmonodecyl ether; Tetraethylene glycol monododecyl ether; Tetraethyleneglycol monotetradecyl ether; Triethylene glycol monodecyl ether;Triethylene glycol monododecyl ether; Triethylene glycol monohexadecylether; Triethylene glycol monooctyl ether, Liquid; Triethylene glycolmonotetradecyl ether; TRITON CF-21, Solution; TRITON CF-32; TRITONDF-12; TRITON DF-16; TRITON GR-5M; TRITON X-100, reduced; TRITON X-302;TRITON X-15; TRITON X-151; TRITON X-207; TRITON X-100; TRITON X-100,Peroxide- and carbonyl-free; TRITON X-114; TRITON X-165 solution; TRITONX-305 solution; TRITON X-405 solution; TRITON X-45; TRITON X-705-70solution; TWEEN 20, Viscous liquid; TWEEN 20, Low-peroxide;Low-carbonyls; TWEEN 20; TWEEN 20, Low-peroxide; Low-carbonyls; TWEEN 20solution, 70% in water; TWEEN 20 solution, 10% in water; TWEEN 21; TWEEN40, Viscous liquid; TWEEN 60; TWEEN 61; TWEEN 65; TWEEN 80, Viscousliquid; TWEEN 80; TWEEN 80; TWEEN 80, Viscous liquid, Low Peroxide;TWEEN 80, Viscous liquid, Preservative Free, Low-peroxide;Low-carbonyls; TWEEN 80 solution, Low Peroxide, 10% (Solution); TWEEN 80solution, Liquid; TWEEN 81; TWEEN 85; Tyloxapol; Tyloxapol; andn-Undecyl β-D-glucopyranoside.

Dosage and Frequency of Administration

The amount of the compound or composition of the invention that will beeffective in conjunction with a particular method of delivery will varye.g., with the nature and severity of the disorder, the route ofadministration, and the device by which the composition is administered.The frequency and dosage will also vary according to factors specificfor each subject, such as age, body, weight, response, and the pastmedical history of the subject. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.Suitable regiments can be selected by one skilled in the art byconsidering such factors and by following, for example, dosages reportedin the literature and recommended in the Physician's Desk Reference(60^(th) ed., 2006).

Exemplary doses include milligram or microgram amounts of the compoundof the invention. In general, the recommended daily dose range of acompound of the invention for the conditions described herein lie withinthe range of from about 0.01 mg to about 100 mg per day, given as asingle once-a-day dose preferably or as divided doses throughout a day.In one embodiment, the daily dose is administered twice daily in equallydivided doses. Specifically, a daily dose range should be from about 0.1micrograms to about 500 micrograms per day, more specifically, betweenabout 0.25 micrograms and about 250 micrograms per day. In managing thepatient, the therapy should be initiated at a lower dose, perhaps about0.1 micrograms, and increased if necessary up to about 500 microgramsper day as either a single dose or divided doses, depending on thepatient's global response. It may be necessary to use dosages of theactive ingredient outside the ranges disclosed herein in some cases, aswill be apparent to those of ordinary skill in the art. Furthermore, itis noted that in instances where a clinician or treating physician isinvolved, such a person will know how and when to interrupt, adjust, orterminate therapy in conjunction with individual subject response.

Different therapeutically effective amounts of a specific compositionmay be applicable for different diseases, as will be readily known bythose of skill in the art. Similarly, different therapeuticallyeffective compounds may be included in a specific composition dependingon the subject's disease. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such disorders, but insufficient to cause,or sufficient to reduce, adverse effects associated with the compoundsof the invention are also encompassed by the above described dosageamounts and dose frequency schedules. Further, when a subject isadministered multiple dosages of a compound or compositions of theinvention, not all of the dosages need be the same. For example, thedosage administered to the subject may be increased to improve theprophylactic or therapeutic effect of the compound or it may bedecreased to reduce one or more side effects that a particular subjectis experiencing.

In various embodiments, the therapies (e.g., prophylactic or therapeuticagents) are administered less than 5 minutes apart, less than 30 minutesapart, 1 hour apart, al about 1 hour apart, at about 1 to about 2 hoursapart, at about 2 hours to about 3 hours apart, at about 3 hours toabout 4 hours apart, at about 4 hours to about 5 hours apart, at about 5hours to about 6 hours apart, at about 6 hours to about 7 hours apart,at about 7 hours to about 8 hours apart, at about 8 hours to about 9hours apart, at about 9 hours to about 10 hours apart, at about 10 hoursto about 11 hours apart, at about 11 hours to about 12 hours apart, atabout 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hoursto 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hoursapart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hoursto 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hourspart. In preferred embodiments, where a physician or clinical visit isinvolved, two or more therapies (e.g., prophylactic or therapeuticagents) are administered within the same subject visit. The therapiescan be administered simultaneously.

In some embodiments, one or more compounds of the invention and one ormore other the therapies (e.g., prophylactic or therapeutic agents) arecyclically administered. Cycling therapy involves the administration ofa first therapy (e.g., a first prophylactic or therapeutic agents) for aperiod of time, followed by the administration of a second therapy(e.g., a second prophylactic or therapeutic agents) for a period oftime, followed by the administration of a third therapy (e.g., a thirdprophylactic or therapeutic agents) for a period of time and so forth,and repeating this sequential administration, i.e., the cycle in orderto reduce the development of resistance to one of the agents, to avoidor reduce the side effects of one of the agents, and/or to improve theefficacy of the treatment.

In other embodiments, administration of the same compound of theinvention may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months. In other embodiments,administration of the same prophylactic or therapeutic agent may berepeated and the administration may be separated by at least at least 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

Topical Dosage Forms

In the current invention, dosage forms containing a compositioncomprising a proinflammatory cytokine inhibitor suitable for treatingmucosal tissues within the upper airways can be formulated as sprays,aerosols, gels, solutions, emulsions, suspensions, or other forms knownto one of skill in the art. See, e.g., Remington's PharmaceuticalSciences; Remington: The Science and Practice of Pharmacy supra;Pharmaceutical Dosage Forms and Drug Delivery Systems by Ansel et al.Lippincott Williams & Wilkins; 7th ed. (1999).

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedby this invention are well known to those skilled in the pharmaceuticaland cosmetic art's, and depend on the particular tissue to which a givenpharmaceutical composition or dosage form will be applied. Typicalexcipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to form lotions,tinctures, creams, emulsions, gels or ointments, which are non-toxic andpharmaceutically acceptable.

Emulsifying agents, preservatives, antioxidants, gel-forming agents,chelating agents, moisturizers, or humectants can also be added topharmaceutical compositions and dosage forms if desired. Examples ofsuch additional are well known in the art. See, e.g., Remington'sPharmaceutical Sciences; Remington: The Science and Practice ofPharmacy; Pharmaceutical Dosage Forms and Drug Delivery Systems, supra.Examples of emulsifying agents include naturally occurring gums, e.g.,gum acacia or gum tragacanth, naturally occurring phosphatides, e.g.,soybean lecithin, and sorbitan monooleate derivatives. Examples ofantioxidants include butylated hydroxy anisole (BHA), ascorbic acid andderivatives thereof, tocopherol and derivatives thereof, butylatedhydroxy anisole and cysteine. Examples of preservatives includeparabens, such as methyl or propyl p-hydroxybenzoate and benzalkoniumchloride. Examples of humectants include glycerin, propylene glycol,sorbitol, and urea. Examples of chelating agents include sodium EDTA,citric acid and phosphoric acid. Examples of gel forming agents includeCarbopol, cellulose derivatives, bentonite, alginates, gelatin, andpolyvinylpyrrolidone. Examples of rehydrating agents include sorbitanesters of fatty acids, polyethylene glycols, glycerol and condensationproducts between sorbitan esters of fatty acids.

In a specific embodiment, the invention provides formulations foradministration to the upper airways. Typically, the compositioncomprises one or more active compound (such as e.g., a proinflammatorycytokine antagonist) in combination with vehicles or the active compoundis incorporated in a suitable carrier system, Pharmaceutically inertvehicles and/or excipients for the preparation of the compositioninclude, e.g., buffering agents such as boric acid or borates, pHadjusting agents to obtain optimal stability or solubility of the activecompound, tonicity adjusting agents such as sodium chloride or borates,viscosity adjusting agents such as hydroxypropyl cellulose,methylcellulose, polyvinylpyrrolidone, polyvinyl alcohols orpolyacrylamide, oily vehicle such as vehicles comprising arachis oil,castor oil and/or mineral oil. Emulsions and suspensions of the activedrug substance may also be presented in the composition. In these cases,the composition may furthermore comprise stabilizing, dispersing,wetting, emulsifying and/or suspending agents.

Additional components may be used prior to, in conjunction with, orsubsequent to treatment with active ingredients of the invention. Forexample, penetration enhancers can be used to assist in delivering theactive ingredients to the tissue. Suitable penetration enhancersinclude, but are not limited to acetone; various alcohols such asethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethylsulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol;pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone,Polyvidone); and urea.

In another embodiment, the invention provides formulations thatincorporate a surfactant. Surfactants as noted above may be added toimprove delivery and/or stability of the composition, minimize heat andagitation induced soluble and insoluble aggregation of proteins, aidrehydration and/or wetting of membranes, and fluidity secretions.Surfactants may be used in conjunction with sugars and divalent cationsto stabilize and protect the composition. Surfactants may be ionic ornonionic in nature. Examples of commercially available surfactants thatmay be used include various water-soluble or insoluble sugar esters suchas TWEEN 80 (polysorbate 80), TWEEN 20, and SPAN 60 (sorbitanmonostearate). Other commercial surfactants that may be incorporatedinclude e.g., pulmonary surfactants.

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery and/or stability of one or more activeingredients. Similarly, the polarity of a solvent carrier, its ionicstrength, or tonicity can be adjusted to improve delivery. Compoundssuch as stearates can also be added to pharmaceutical compositions ordosage forms to alter advantageously the hydrophilicity or lipophilicityof one or more active ingredients to improve delivery. In this regard,stearates can also serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates, or solvates ofthe active ingredients can be used to adjust further the properties ofthe resulting composition.

Controlled Release Transdermal Dosage Forms

The current invention also provides controlled release dosage forms ofcompositions comprising one or more proinflammatory cytokine inhibitor.As used herein, the terms “controlled release dosage form” and“controlled release formulation” are used interchangeably to refer to(i) formulations which create a substantially constant concentration ofthe drug at the site of administration over an extended period of time,(ii) formulations that after a predetermined lag time create asubstantially constant concentration of the active compound(s) or drugs)over an extended period of time, (iii) formulations that sustain drugaction during a predetermined tune period by maintaining a relatively,constant, effective drug level with concomitant minimization ofundesirable side effects associated with fluctuations in local levels ofthe active drug substance (e.g., the spatial placement of a controlledrelease composition adjacent to or in the diseased tissue or organ,and/or (iv) formulations which attempt to target drug action by usingcarriers or chemical derivatives to deliver the drug to a particulartarget cell type. Controlled release formulations are also known in theart as, for example, “sustained release”, “prolonged release”,“programmed release”, “time release”, “rate-controlled” and/or “targetedrelease” formulations.

Pharmaceutical compositions intended to be administered as controlledrelease forms may be presented in any suitable dosage forms, especiallyin dosage forms intended expressly for upper airways. Such dosage formscan be used to provide controlled-release of one or more activeingredients using, for example, polymer matrices, gels, permeablemembranes, osmotic systems, multilayer coatings, microparticles,nanoparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Fortransdermal administration, suitable ingredients will includepolyhydroxy acids such as polylactic acid, polyglycolic acid and othercopolymers synthetic polymers, polyorthoesters, polyanhydrides, andpolyphosphazenes, and natural polymers such as collagen, polyaminoacids, albumin and other proteins, alginate and other polysaccharides,and combinations thereof (see U.S. Pat. No. 5,814,599).

Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the compounds and compositions of the invention.Examples include, but are not limited to, those described in U.S. Pat.Nos. 3,536,809; 3,598,123; 3,845,770; 3,916,899; 4,008,719; 5,059,595;5,073,543; 5,120,548; 5,354,556; 5,591,767; 5,639,476; 5,674,533, and5,733,566, each of which is incorporated herein by reference in theirentirety.

Articles of Manufacture

The invention further encompasses articles of manufacture. A typicalarticle of manufacture of the invention comprises a unit dosage form ofa composition or compound of the invention. In one embodiment, the unitdosage form is a container, preferably a sterile container, containingan effective amount of a composition or compound of the invention and apharmaceutically acceptable carrier or excipient. The article ofmanufacture can further comprise a label or printed instructionsregarding the use of composition or compound or other informationalmaterial that advises the physician, technician, consumer, subject, orpatient on bow to prevent, treat or derive a beneficial resultpertaining to the disorder in question. The article of manufacture caninclude instructions indicating or suggesting a dosing regimenincluding, but not limited to, actual doses, monitoring procedures, andother monitoring information. The article of manufacture can alsofurther comprise a unit dosage form of another prophylactic ortherapeutic agent, for example, a container containing an effectiveamount of another prophylactic or therapeutic agent. In a specificembodiment, the article of manufacture comprises a container containingan effective amount of a composition or compound of the invention and apharmaceutically acceptable carrier or excipient and a containercontaining an effective amount of another prophylactic or therapeuticagent and a pharmaceutically acceptable carrier or excipient. Examplesof other prophylactic or therapeutic agents include, but are not limitedto, those listed above. Preferably, the packaging material and containerincluded in the article of manufacture are designed to protect thestability of the product during storage and shipment.

Article of manufacture of the invention can further comprise devicesthat are useful for administering the unit dosage forms. Examples ofsuch devices include, but are not limited to, syringes, atomizers,metered dose, and nonmetered dose inhalers.

Articles of manufacture of the invention can further comprisepharmaceutically acceptable vehicles or consumable vehicles that can beused to administer one or more active ingredients (e.g., a compound ofthe invention). For example, if an active ingredient is provided in asolid form that must be reconstituted for upper airways administration,the article of manufacture can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved. For upperairways administration, a particulate-free sterile solution ispreferred. Examples of pharmaceutically acceptable vehicles include, butare not limited to: Water for Injection USP; aqueous vehicles such asbut not limited to, Sodium Chloride Injection, Ringer's Injection,Dextrose Injection, Dextrose and Sodium Chloride Injection, and LactatedRinger's Injection; water-miscible vehicles such as, but not limited to,ethyl alcohol, polyethylene glycol, and polypropylene glycol; andnon-aqueous vehicles such as, but not limited to, corn oil, cottonseedoil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, andbenzyl benzoate.

In another embodiment of the invention, articles of manufacture and kitsare provided containing materials useful for treating the pathologicalconditions described herein, including rhinosinusitis and associatedproblems. The article of manufacture comprises a container with a label.Suitable containers include, for example, bottles, vials, and testtubes. The containers may be formed from a variety of materials such asglass or plastic. The container holds a composition having at least oneactive compound that is effective for treating, for example,rhinosinusitis, or complications of rhinosinusitis. The active agent inthe composition is a proinflammatory cytokine inhibitor, and thecomposition may contain one or more active agents. The label on thecontainer indicates that the composition is used for treating, forexample, rhinosinusitis, and may indicate directions for in viva use,such as those described above.

One embodiment of the invention is a kit that includes a container, adelivery device, including a microcatheter as described above; a labelon said container and/or delivery device; a composition contained withinsaid container or delivery device that includes one or more activeingredients as described herein, a pharmaceutically-acceptable carrier;and instructions for using said composition for expressly treating upperairways disease or pathologic conditions of the upper airways.

In a preferred embodiment of the invention, articles of manufacture andkits are provided that specifically incorporate a nasal inhaler. Thenasal inhaler preferably is effective at delivering a compound orcomposition of the invention to specific sites within the nose, whileminimizing drug distribution to the lungs. The delivery device mayincorporate certain parts including but not limited to filters, needles,syringes, valves, atomizers, nasal adapters, electronic nebulizers,meters, heating elements, reservoirs, a power source(s); and packageinserts with instructions for use.

The kit of the invention comprises the container described above and mayalso include a second or third container comprising a pharmaceuticallyacceptable carrier or buffer, dosing reservoir, or a surfactant. It mayfurther include other materials desirable from a commercial and userstandpoint, including other buffers, diluents, and a device for deliveryexpressly to the upper airways incorporating filters, needles, syringes,valves, atomizers; and package inserts with instructions for use.

Delivery Devices

A one aspect of the invention is the local delivery expressly to theupper airways of the composition and the delivery device thataccomplishes said dosing. Delivery devices of the current inventionprovide methods for the local delivery of the composition whereby one ormore pharmacologically active agents or local treatments of thecomposition may have local effects expressly in the vicinity of themucosa of the upper airways.

Various instruments may be used to administer a pharmaceuticalcomposition for treatment of rhinosinusitis-related disorders, and willbe apparent to those skilled in the art. In one embodiment of theinvention, a functional endoscope and microcatheter may be employedtogether to access a desired target nasal region via the nasal passages,and, when necessary a sinus via an ostium. This microcatheter system maybe operated to apply bioactive agent(s) locally, including therapeuticsto treat nasal and sinus disorders such as sinusitis, rhinosinusitis,and sino-nasal polyps.

In another embodiment, a composition containing one or more therapeuticagents described herein is directly administered to the upper airways.Such administration may be carried out via use of an aerolizer, whichcreate an aerosol containing the composition and which may be directlyinstalled into the upper airways. Exemplary aerolizers are disclosed inU.S. Pat. Nos. 5,579,758; 6,041,775; 6,029,657; 6,016,800; 5,506,789;and 5,594,987 all of which are herein incorporated by reference in theirentirety. The invention thus provides for the methods of administeringcompositions containing one or more proinflammatory cytokine inhibitorsdirectly to the upper airways by an aerolizer.

In an alternate embodiment, the device is an aerosolizer attached to apressure generator for delivery of liquid as an aerosol and which can bepositioned in close proximity to the target in the upper airways. Theaerolizer has a sleeve with a first and second end and substantiallylongitudinally extending opening therethrough, with an aerosol generatordisposed within the opening of the sleeve member, and a pressuregenerator connected with the sleeve member. Therefore, in anotherembodiment, such an aerolizer is a syringe with a valve, a reservoircontaining the composition at the tip of the syringe, and a thincapillary connected to the reservoir. The tip of the capillary isinstalled into the upper airways for administration. Air is pumpedthrough the syringe into the reservoir and through the capillary therebydelivering compositions of the instant invention to the upper airways.

In yet another embodiment, such an aerolizer has a substantiallyelongated sleeve member, a substantially elongated insert, and asubstantially elongated body member. The sleeve member includes athreaded inner surface, which is adapted to receive the insert, which isa correspondingly threaded member. The threaded insert provides asubstantially helical channel. The body member includes a cavity on itsfirst end, which terminates by an end wall at its second end. The endwall includes an orifice extending therethrough. The body member isconnected with the sleeve member to provide the aerosolizer. Theaerosolizer is sized to accommodate insertion into the upper airways ofa subject for use of the device to administer composition containing aproinflammatory cytokine inhibitor. For operation of the device, theaerosolizer is connected by a suitable tube to a liquid pressure driverapparatus. The liquid pressure driver apparatus is adapted to passliquid material that is sprayed from the aerosolizer.

In an alternate embodiment, a powder dose composition containing one ormore proinflammatory cytokine inhibitors is directly administered to theupper airways via use of a powder dispenser. Exemplary powder dispensersare disclosed in U.S. Pat. Nos. 5,513,630; 5,570,686 and 5,542,412, allof which are herein incorporated in their entirety. Such a dispenser isadapted to be brought into connection with an actuator, which introducesan amount of a gas for dispensing the powder dose. The dispenserincludes a chamber for receiving the powder dose and a valve forpermitting passage of the powder dose only when the actuator introducesthe gas into the dispenser. The powder dose is passed from the dispenserto the upper airways of the subject via a tube.

Direct administration of composition to the upper airways can also beachieved sinus catheters and a preferred embodiment is the use of theYAMIK sinus catheter. The invention also encompasses directadministration of composition to the upper airways using amicrocatheter.

In a further preferred embodiment, the present invention provides anadapted method and system for delivering and/or improving the deliveryof bioactive agents to tissue sites within the nasal passages includingthe paranasal sinuses. Typically, these sites will be characterized byinflammation, and in turn, will suffer from reduced or ineffectiveperfusion by bodily fluids, such as blood or other interstitial fluids,making these sites difficult to reach with systemic or aerosolsbioactive substances including therapeutics, as compared to othertissues.

In accordance with the current invention, aerosolizing microcathetersare contemplated for the direct delivery of bioactive agents to thenasal passages and into the paranasal sinuses.

In one embodiment, this delivery system incorporates a liquid-pressuretype of sprayer to avoid those problems associated with the commonair-pressure type of sprayer, particularly the unwanted generation of alarge mount of vehicle gas which may be injurious to the airways.

The present invention also incorporates the use of a new high-pressuresyringe which described in U.S. Pat. No. 6,016,800, which isincorporated by reference herein in its entirety. This syringe iscapable of withstanding internal pressures far in excess of the 2,000psi operating pressures required for operation of the microcatheteraerosolizer of the present invention.

Another object of the present invention is to provide a sprayer deviceof sufficient size to permit insertion into the working channel of anendoscope, nasal passages, and partial or complete insertion into theostium of a paranasal sinus.

The present invention also provides specifically a method of using themicrocatheter aerosolizer and high-pressure syringe, described above.The method includes the steps of connecting the microcatheteraerosolizer with a first end of a hollow tube member and connecting thesecond end of the hollow tube member with the liquid pressure driverapparatus. The method further includes the steps of placing themicrocatheter aerosolizer in the nasal passages or ostium of one or moreparanasal sinus, and then activating the liquid pressure driverapparatus for spraying a bioactive liquid material.

Numerous drug delivery devices capable of drug distribution to the upperairways can use a liquid, semisolid, and solid composition as describedand investigated with respect to their deposition in the upper airways,by Vidgren and Kublik (Vidgren et al. Int. J. Pharmaceutics, 42:211-216(1988)). These investigators found the site of deposition and thedeposition area depend on several parameters related to the deliverydevice, such as mode of administration, particle size of the formulationand velocity of the delivered particles. They describe several in vitroand in vivo methods that may be used by one of ordinary skill in the artto study distribution and clearance of intranasally deliveredtherapeutics, all of which is incorporated in its entirety, herein.Thus, any of these devices may be selected for use in the currentinvention, given one or more advantages for a particular indication,technique, and subject. These delivery devices include but are notlimited to devices producing nasal aerosols (metered-dose inhalers(MIAs)), nasal sprays (metered-dose spray pumps) and other metered andnonmetered dose atomizers (squeeze) bottles.

In general, current container-closure system designs for inhalationspray drug products include both premetered and device-meteredpresentations using mechanical or power assistance and/or energy frompatient inspiration for production of the spray plume. Premeteredpresentations may contain previously measured doses or a dose fractionin some type of units (e.g., single or multiple blisters or othercavities) that are subsequently inserted into the device duringmanufacture or by the patient before use. Typical device-metered unitshave a reservoir containing formulation sufficient for multiple dosesthat are delivered as metered sprays by the device itself when activatedby the patient.

In a preferred embodiment of the current invention, the delivery deviceis able to distribute the composition expressly to the mucosa of theupper airways in a subject in need of such treatment, with a minimalamount of composition reaching the pharynx and lower airways.

The current invention also incorporates multidose metering ornonmetering spray pumps that are specially suited for repeatedadministrations and can provide numerous doses (typically 50 to up toabout 130 microliters or more) either with or without stabilizers andpreservatives. Typically, such devices are used to treat acute,subacute, chronic and recurrent upper airways diseases.

Another embodiment of the current invention incorporates the use ofmultidose metering and nonmetering spray pumps working as closedsystems. These systems may prevent air from entering into the containerthat may contaminate the composition.

Still another embodiment of the current invention incorporates the useof metering or nonmetering spray pumps employing filters to preventbacterial contamination of the composition, especially when usingmultidose devices.

Yet another embodiment of the current invention incorporates the use ofbidirectional nasal drug delivery as described by Djupesland et al.(Innovations in Pharmaceutical Technology). This device is inserted intoone nostril by a sealing nozzle and the subject blows into themouthpiece. The combination of closed soft palate and sealed nozzlecreates an airflow that enters one nostril, turns 180° through thecommunication pathway and exits through the other nostril. Smallparticles are delivered during exhalation and are prevented fromentering the lower airways.

Administration of a composition comprised of a bioactive agent as aspray can be produced by forcing a suspension or solution of at leastone proinflammatory cytokine inhibitor through a nozzle under pressure.The nozzle size and configuration, the applied pressure, and the liquidfeed rate earl be chosen to achieve the desired output and particle sizeto optimize deposition expressly in the upper airways. An electrospraycan be produced, for example, by an electric field in connection with acapillary or nozzle feed. Advantageously, particles of at least oneproinflammatory cytokine inhibitor composition delivered by a sprayerhave a particle size less than about 30 microns, preferably in the rangebelow 20 microns, and most preferably, about 5 to 20 microns, but otherparticle sizes may be appropriate depending on the device, composition,and subject needs.

Commercially available nebulizers for liquid formulations, including jetnebulizers and ultrasonic nebulizers may also be useful foradministration when adapted expressly for upper airways delivery. Liquidformulations may be directly nebulized and lyophilized power nebulizedafter reconstitution.

Alternatively, the composition may be aerosolized using a metered doseinhaler, or inhaled as a lyophilized and milled powder. In addition, theliquid formulation of composition may be instilled through catheters,including sinus catheters placed directly into the sinus in subjects whohave undergone surgical antrostomies or via endoscope into the sinuses.Direct administration of composition to the upper airways can also beachieved with the YAMIK sinus catheter.

In one embodiment of the present invention, a bioactive agent may beadministered by a metered dose inhaler. In a metered dose inhaler (MDI),a propellant, at least one proinflammatory cytokine inhibitor, andvarious excipients or other compounds are contained in a canister as amixture including a liquefied compressed gas. Actuation of the meteringvalve releases the mixture as an aerosol, preferably containingparticles in the size range of less than about 30 microns. The desiredaerosol particle size can be obtained by employing a formulation ofantibody composition protein produced by various methods known to thoseof skill in the art, including jet-milling, spray drying, critical pointcondensation, or other methods well known to one of ordinary skill inthe art.

Compositions of at least one bioactive agent (e.g., a proinflammatorycytokine inhibitor) for use with a metered-dose inhaler device caninclude a finely divided powder containing at least one proinflammatorycytokine inhibitor as a suspension in a non-aqueous medium, for example,suspended in a propellant with the aid of a surfactant or solubilizingagent. The propellant can be any conventional material including but notlimited to chlorofluorocarbon, a hydrochlorofluorocarbon, ahydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane,dichlorodifluoromethane, dichlorotetrafluoroethanol and1,1,1,2-tetrafluoroethane, HFA-134a (hydrofluroalkane-134a), HFA-227(hydrofluroalkane-227). Hydrofluorocarbon is a preferred propellant. Asurfactant can be chosen to stabilize the at least one proinflammatorycytokine inhibitor as a suspension in the propellant, to protect theactive agent against chemical degradation. In some cases, solutionaerosols are preferred using solvents such as ethanol for morewater-soluble proinflammatory cytokine inhibitors. Additional agentsincluding a protein can also be included in the composition.

The current invention also contemplates the combined use of amicrocatheter device for initial therapy administered by a physician,followed by a nasal spray device for self-administration by the subject.In any event, the microcatheter may be used once, twice, or multipletimes prior to the use of the self-administered nasal spray.

One of ordinary skill in the art will recognize that the methods of thecurrent invention can be achieved by nasal administration of at leastone bioactive agent including one or more proinflammatory cytokineinhibitor compositions via devices not described herein.

The current invention also incorporates unit-dose metering andnonmetering spray devices that are specially suited for singleadministration. These devices are typically used for acute short-termtreatments (i.e., acute sinusitis) and single-dose delivery (i.e., longacting compositions) and can accommodate a liquid, powder, or mixture ofboth formulations of the composition. However, in certain circumstances,these unit dose devices may be preferred over multidose devices whenused repeatedly in a particular way. Such uses may include but are notlimited to repeated surgical procedures where a sterile device ispreferred, applications where a syringe is preferred includingdistribution of composition through sinus drainage tubes, ordistribution of composition through an endoscope. These examples are notintended to be limiting and one skilled in the art will appreciate thatother options exist for delivery of the composition expressly to theupper airways and these are also incorporated herein.

Another example of a potentially suitable delivery device of the currentinvention is described in the literature (SINUNEB System) and isincluded herein. This nebulizer has been adapted for nasal inhalationwhere the composition may be aerosolized to a particle size small enoughto disperse within the upper airways including the sinus cavities, yetlarge enough to be deposited in the “sinuses” and not in the pharynx andlower airways.

Still other delivery devices employ electronic atomization for nasaldelivery of various pharmaceutical drug products (e.g., VIANASE ID) andare included herein.

In general, pump spray weight delivery should control the weight of theindividual sprays to within about 15 percent of the target weight andtheir mean weight to within about 10 percent of the target weight.However, for small dosage pumps (e.g., 20 microliters) other criteriamay be acceptable.

Another embodiment of the invention provides for a syringe prefilledwith the composition appropriate for treating the upper airways diseaseof the subject. Said prefilled syringe may be sterile or nonsterile andused in dose administration prior to surgery, during intraoperativeprocedures and post-operatively to a subject in need of upper airwaystherapy.

Importantly, another embodiment of the invention provides for the use ofthe current invention in combination with the systemic dosing of abioactive agent such as a proinflammatory cytokine inhibitor for acutedisease or certain cases where the combination of systemic and localadministration of the bioactive agent may work best to relieve thesymptoms of the subject in need of therapy.

For example, the proinflammatory cytokine inhibitor may be administeredsystemically via subcutaneous or intravenous injection (or some othersystemic route of administration) for one or more dosing periods incombination with a topical or systemic antibiotic, followed by the localdelivery expressly to the upper airways of the composition as describedherein. One of ordinary skill in the art will recognize that the methodsof the current invention can be achieved by upper airway administrationof at least one proinflammatory cytokine inhibitor composition viadevices not described herein.

Microcatheters for Treating Upper Airways Disorders

Other preferred embodiments include composite microcatheters used foraccess and advancement into the nasal cavity and/or a paranasal sinuscomprising at least one flexible, tubular communicating element with anouter diameter of 1500 micron or less, alternatively, 1000 microns orless, preferably 500 microns or less, with proximal and distal ends, andsized to fit within the tissue space; a proximal connector forintroduction of bioactive materials including therapeutics, and areinforcing member in conjunction with the communicating element. Thetubular communicating element has proximal and distal ends and is sizedto fit within the tissue space. These systems may also utilize areservoir. The reservoir may store gas, fluid, or powder, and serve toforce the bioactive materials through the microcatheter. If thebioactive materials are stored within the reservoir, it can beconstructed with materials that are compatible with the bioactive agentsused. In addition, the proximal end of the tubular communicating elementhas a connector or linkage, which is compatible with a reservoir forintroduction of bioactive materials including therapeutics, and areinforcing member in conjunction with the communicating element. In oneembodiment, the bioactive material may be forced from the reservoirthrough the microcatheter. An example of such a reservoir and deliverydevice is a syringe attached by a leur lock to the microcatheter soforce can be applied to empty the syringe and deliver the biomaterial tothe target site.

Optionally, microcatheters used in this invention can have regions ofvarying characteristics, including varying porosity, rigidity, and thelike, for instance those that vary between sequential and adjacent, orsuitably spaced, longitudinal sections, or in or any other suitablepattern. Such variations can also be used to provide regions of greaterrigidity or varying structure (e.g., fluted), in order facilitate theirplacement with or without an endoscope in the nasal passages, andpartially or completely into the ostium of a paranasal sinus.

Other embodiments, include composite microcatheters used to access andadvance into the nasal cavity and/or paranasal sinus comprising at leastone flexible, tubular communicating element with an outer diameter of1500 microns or less, alternatively, 1000 microns or less, preferably500 microns or less, with proximal and distal ends, and sized to fitwithin the tissue space; a proximal connector for introduction ofbioactive materials including therapeutics, via a reservoir, and areinforcing member in conjunction with the communicating element.

One embodiment is a microcatheter having a reinforcing member thatprovides for greater axial and flexural stiffness at the proximal end ofthe microcatheter and lower axial and flexural stiffness to the distalend. Another embodiment is a microcatheter having a reinforcing elementformed of metal, preferably flexible metal. Another embodiment is amicrocatheter having a communicating element formed of a flexiblepolymer and a reinforcing member formed of metal.

Another embodiment is a microcatheter having two or more communicatingelements in concentric or parallel alignment. Optionally, microcathetersused in this invention comprise two communicating elements where thesecond communicating element is located within the lumen of the firstcommunicating element. Another embodiment is a microcatheter having acommunicating element formed of a segment of tubing.

Another embodiment is a microcatheter having two or more reinforcingelements. Another embodiment is a microcatheter having a reinforcingelement in the form of a coil or a reinforcing element that is taperedtoward the distal end of the microcatheter.

One embodiment is a microcatheter designed to fit within an ostia of aparanasal sinus. Another embodiment is a microcatheter having a distaltip with a rounded leading edge.

Another embodiment is a microcatheter having a communicating element anda reinforcing element that are joined by an outer sheath. Anotherembodiment is a microcatheter having an outer sheath formed of heatshrink tubing. Another embodiment is a microcatheter having art outersheath that is thermally fused to the communicating element(s).Optionally, the microcatheter may have a communicating element and areinforcing element that are joined with an adhesive. Another embodimentis a microcatheter having a communicating element and a reinforcingelement that are bonded through non-adhesive means such as thermal orultrasonic welding.

One embodiment is a composite microcatheter for access and advancementinto a paranasal sinus comprising at least one flexible, tubularcommunicating element with an outer diameter of 1000 microns or less,with proximal and distal ends, to fit within the tissue space; and acoiled metal reinforcing member attached to the communicating element;wherein the communicating element is formed of a flexible polymer or asuperelastic metal alloy.

Another embodiment is a composite microcatheter for access andadvancement partially or completely into a paranasal sinus comprising atleast one flexible, tubular communicating element with an outer diameterof 1500 microns or less, alternatively, 1000 microns or less, preferably500 microns or less, with proximal and distal ends, and a fluidcommunicating lumen sized to fit within the tissue space; a proximalconnector, and reservoir, for introduction of fluid, where themicrocatheter provides means for the delivery of fluid to the distal tipof the microcatheter.

Another embodiment is a microcatheter for access and advancement into aparanasal sinus comprising at least one flexible, tubular communicatingelement with an outer diameter of 1000 microns or less, with proximaland distal ends, and a fluid communicating lumen sized to fit within anostia of a paranasal sinus, and a reinforcing member, whereby themicrocatheter provides means for the delivery of a therapeutic or othermaterials at the distal tip of the microcatheter to affected nasaltissues and/or paranasal sinuses.

The method and instruments of the invention, used separately ortogether, can be employed to treat a variety of conditions and targetsites, including sino-nasal target sites. Exemplary target sites includeeither or both nostrils, the left or right lower nasal cavity, the leftor right upper nasal cavity, the sinuses, especially those sinuses thatare accessible via the nasal cavity and, if accessible, the frontal,ethmoidal, sphenoidal and maxillary sinuses.

Various suitable instruments for treating one or more target sites, aswell as other suitable target sites, will be apparent to those skilledin the art in light of the disclosure herein.

The above-described devices and methods of delivery of bioactivematerials, preferably one or more therapeutic agent(s), provide a numberof unexpected advantages over the existing treatments relying onaerosols or nasal sprays and the associated devices and methods to treatnasal disease including rhinitis and sinusitis. The advantages include,but are not limited to, the simple and economical, yet reliable,operation of the devices, that improve the distribution of materialsincluding therapeutics to the nasal region including the paranasalsinuses.

Aerosolizing Microcatheters

In particular, a further embodiment of the present invention is a newuse for the “intratracheal aerosolizer” device which methodologyinvolves the generation of a fine aerosol at the tip of a long,relatively thin tube that is suitable for insertion into the trachea.Thus, the present invention provides a new method of use for thisaerosolizer technology in a microcatheter as adapted herein, for use inthe upper airways in the prevention, treatment, and care of upperairways disorders including rhinitis, sinusitis, and sino-nasal polyps.

In one embodiment of the invention, an aerosolizing microcatheter isused to administer a composition containing a pro-inflammatory cytokineinhibitor. Examples of such catheters and their use, termed“intratracheal aerosolization,” which involves the generation of a fineaerosol at the tip of a long, relatively thin tube that is suitable forinsertion into the trachea, are disclosed in U.S. Pat. Nos. 5,579,758;3,594,987; 5,606,789; 6,016,800; and 6,041,775.

In one embodiment of the invention, a composition comprising aproinflammatory cytokine inhibitor is administered by intratrachealaerosolization. Thus, the present invention provides for the use ofintratracheal aerosolization, for the prevention; treatment, and care ofupper airways disorders including rhinitis, sinusitis, and sine-nasalpolyps.

In one embodiment, the aerolization catheter is of sufficient size topermit insertion into the ostium of a paranasal sinus or the nasalpassages to improve the delivery of bioactive agents in disorders of theupper airways, including sinusitis and rhinitis is used. Furthermore,such a microcatheter spray device is capable of delivering an effectiveamount of material in a short length of time to the nasal passagesand/or paranasal sinuses. In addition, such a microcatheter spray devicecapable of delivering relatively small droplets and at relatively lowpressures to the nasal passages and/or paranasal sinuses and is capableof delivering bioactive agents to the nasal passages and/or paranasalsinuses that is easy to operate and clean.

In another preferred embodiment, a microcatheter aerosolizer is adaptedby sizing the microcatheter between about 1500 and 1000 microns,alternatively, between about 1500 and 1000 microns, alternatively,between about 1000 microns and 50 microns, preferably between about 500microns and 50 microns, for spraying bioactive liquid materials afterpartial or complete insertion into the ostium of a paranasal sinus, orinto the nasal passages.

The microcatheter with aerosol generating capabilities is placed intoconnection with a liquid pressure driver apparatus for delivering of theliquid material. Said apparatus can be a reservoir, or syringe. Thereservoir may be disposable or easily cleaned and reusable. Inaccordance with the present invention, the microcatheter aerosolizercomprises a generally elongated sleeve member which defines a first endand a second end and includes a longitudinally extending opening. Thefirst end of the sleeve member is placed in connection with the liquidpressure driver apparatus. A generally elongated insert is alsoprovided. The generally elongated insert defines a first end and asecond end and is received within at least a portion of thelongitudinally extending opening of the sleeve member. The insertincludes an outer surface which has at least one substantially helicalchannel provided surrounding its outer surface which extends from thefirst end to the second end. The substantially helical channel of theinsert is adapted to pass the liquid material which is received by thesleeve member. A generally elongated body member is also included whichis in connection with the sleeve member. The body member includes acavity provided in its first end which terminates at an end wall whichis adjacent its second end. The end wall is provided having an orificetherein for spraying the liquid material which is received from theinsert. The portions of the sleeve member, insert and body member, incombination, axe of sufficient size for partial or complete entry into aparanasal sinus ostium.

A further advantage of the current microcatheter aerosolizer relates tothe size of the particles produced by the device; for example, apreferred embodiment is described herein in which the device describedoperates at a pressure of about 2,000 psi and produces particles with amedian mass diameter of about 12 microns, or larger, well adapted todeposition in the upper airways yet good distribution in the paranasalsinuses.

In one embodiment, this delivery system incorporates a liquid-pressuretype of sprayer to avoid those problems associated with the commonair-pressure type of sprayer, particularly the unwanted generation of alarge mount of vehicle gas, which may be injurious to the airways. Thepresent invention also provides a novel administration device adaptedfor the purposes of delivering bioactive agents as solutions directlyinto the nasal passages and the sinuses.

The microcatheter with aerosol generating capabilities is placed intoconnection with a liquid pressure driver apparatus for delivering of theliquid material. Said apparatus can be a reservoir, or syringe. Thereservoir may be disposable or easily cleaned and reusable. Inaccordance with the present invention, the microcatheter aerosolizercomprises a generally elongated sleeve member, which defines a first endand a second end and includes a longitudinally extending opening. Thefirst end of the sleeve member is placed in connection with the liquidpressure driver apparatus. A generally elongated insert is alsoprovided. The generally elongated insert defines a first end and asecond end and is received within at least a portion of thelongitudinally extending opening of the sleeve member. The insertincludes an outer surface which has at least one substantially helicalchannel provided surrounding its outer surface which extends from thefirst end to the second end. The substantially helical channel of theinsert is adapted to pass the liquid material, which is received by thesleeve member. A generally elongated body member is also included whichis in connection with the sleeve member. The body member includes a;cavity provided in its first end which terminates at an end wall whichis adjacent its second end. The end wall is provided having an orificetherein for spraying the liquid material which is received from theinsert. The portions of the sleeve member, insert and body member, incombination, are of sufficient size for partial or complete entry into aparanasal sinus ostium.

The present invention also provides specifically a method of using themicrocatheter aerosolizer described above. The method includes the stepsof connecting the microcatheter aerosolizer with a first end of a hollowtube member and connecting the second end of the hollow tube member withthe liquid pressure driver apparatus. The method further includes thesteps of placing the microcatheter aerosolizer in the nasal passages orostium of one or more paranasal sinus, and then activating the liquidpressure driver apparatus for spraying a bioactive liquid material.

In a further embodiment of the present invention new use for themicrocatheter aerosolizer device (U.S. Pat. Nos. 6,016,800 and6,029,657) adapted for nasal and paranasal sinus delivery and uses todeliver bioactive agents in the treatment, prevention, and diagnosis ofupper airways disorders. One advantage of this microcatheter aerosolizeris the potential small size (0.014″ in diameter), and thus capable ofbeing easily inserted into the working channel of a human flexible (1 to2 mm in diameter) or ridged endoscope and thereby directed partially orcompletely into the ostium of a paranasal sinus.

This delivery system is further capable of being flexed through anglesand radii of curvature similar to those found at the flexible tip of anendoscope, without exceeding the elastic limit of the aerosolizer orputting undue strain on the flexing mechanism of the endoscope.

A further advantage of the current microcatheter aerosolizer relates tothe size of the particles produced by the device; for example, apreferred embodiment is described herein in which the device describedoperates at a pressure of about 2,000 psi and produces particles with amedian mass diameter of about 12 microns, or larger, well adapted todeposition in the upper airways yet good distribution in the paranasalsinuses.

The present invention also incorporates the use of a new high-pressuresyringe which described in U.S. Pat. No. 6,016,800, which isincorporated by reference herein, in its entirety. This syringe iscapable, of withstanding internal pressures far in excess of the 2,000psi operating pressures required for operation of the microcatheteraerosolizer of the present invention.

Another object of the present invention is to provide a sprayer deviceof sufficient size to permit insertion into the working channel of anendoscope, nasal passages, and partial or complete insertion into theostium of a paranasal sinus.

The present invention also provides specifically a method of using themicrocatheter aerosolizer and high-pressure syringe, described above.The method includes the steps of connecting the microcatheteraerosolizer with a first end of a hollow tube member and connecting thesecond end of the hollow tube member with the liquid pressure driverapparatus. The method further includes the steps of placing themicrocatheter aerosolizer in the nasal passages or ostium of one or moreparanasal sinus, and then activating the liquid pressure driverapparatus for spraying a bioactive material.

Additional embodiments of the present invention include methods ofpreparation of liquid solutions of proinflammatory cytokine inhibitorthat are protected from thermally induced aggregation of the inhibitorcomponent of a composition.

The method and instruments of the invention, used separately ortogether, can be employed to treat a variety of conditions and targetsites, including sino-nasal target sites. Exemplary target sites includeeither or both nostrils, the left or right lower nasal cavity, the leftor right upper nasal cavity, the sinuses, especially those sinuses thatare accessible via the nasal cavity and, if accessible, the frontal,ethmoidal, sphenoidal and maxillary sinuses. Various suitableinstruments (including instruments described in U.S. Pub. App.20050107853 for treating one or more target sites, as well as othersuitable target sites, will be apparent to those skilled in the art inlight of the disclosure herein.

The above-described devices and methods of delivery of bioactivematerials, preferably therapeutic agent(s), provide a number ofunexpected advantages over the existing treatments relying on aerosolsor nasal sprays and the associated devices and methods to treat nasaldisease including rhinitis and sinusitis. The advantages include, butare not limited to, the simple and economical, yet reliable, operationof the devices, that improve the distribution of materials includingtherapeutics to the nasal region including the paranasal sinuses.

Methods of Treatment

Described herein are uses of the compounds and compositions of theinvention for attaining a beneficial effect pertaining to upper airwaysdisease, providing a beneficial effect pertaining to such diseases, orone or more symptoms thereof. The methods comprise administering to asubject in need thereof a prophylactically or therapeutically effectiveamount of a composition comprising a pro inflammatory cytokineinhibitor. For example, administration of such compounds can be via oneor more of the pharmaceutical compositions of the invention.

As used herein, the terms “subject” and “patient” are usedinterchangeably herein. The terms “subject” and “subjects” refer to ananimal, preferably a mammal including a non-primate and a primate (e.g.,a monkey such as a cynomolgous monkey, a chimpanzee, and a human), andmore preferably a human.

In one embodiment, a subject in need of prevention, treatment,management, or amelioration of a disorder or a symptom thereof is asubject that has the disorder, that is known to be at risk of thedisorder, has been diagnosed with the disorder, has previously recoveredfrom the disorder, or is resistant to current therapy. In particularembodiments, the subject is an animal, preferably a mammal, and morepreferably a human, that is predisposed and/or at risk because of agenetic factor(s), an environmental factor(s), or a combination thereofto develop the disorder. In yet another embodiment, the subject isrefractory or non-responsive to one or more other treatments for adisorder. As used herein, the terms “non-responsive” and “refractory”describe patients treated with a currently available modality (e.g., aprophylactic or therapeutic agent) for a disorder, which is notclinically adequate to relieve one or more symptoms associated with suchdisorder. Typically, such patients require additional therapy toameliorate the symptoms associated with their disorder. In yet anotherembodiment, the subject is an immunocompromised or immunosuppressedmammal, such as a human. In preferred embodiments of the invention, thedisorder is rhinosinusitis or a symptom associated with rhinosinusitis.

As used herein, the terms “modality”, modalities”, “therapies” and“therapy” can refer to any protocol(s), method(s), and/or agent(s) thatcan be used in the prevention, treatment, management, or amelioration ofa disorder or one or more symptoms thereof. In a certain embodiments,the terms “modality”, modalities“, “therapy” and therapies” refer tochemotherapy, surgery, biological therapy, immunotherapy and/or othertherapies useful in the prevention, management, treatment oramelioration of a disorder or one or more symptoms thereof.

As used herein, the terms “treat”, “treatment” and “treating” refer tothe reduction or amelioration of the progression, severity and/orduration of a disorder, or the amelioration of one or more symptomsthereof resulting from the administration of one or more modalities(e.g., one or more therapeutic agents such as a compound or compositionof the invention).

As used herein, the terms “prevent,” “preventing” and “prevention” referto the prevention or inhibiting of the recurrence, onset, or developmentof a disorder or a symptom thereof in a subject resulting from theadministration of a therapy (e.g., a prophylactic or therapeutic agent),or the administration of a combination of therapies (e.g., a combinationof prophylactic or therapeutic agents).

As used herein, the terms “manage,” “managing,” and “management” referto the beneficial effects that a subject derives from a therapy (e.g., aprophylactic or therapeutic agent), while not resulting in a cure of thedisease. In certain embodiments, a subject is administered one or moremodalities (e.g., one or more prophylactic or therapeutic agents) to“manage” a disease so as to prevent the progression or worsening of thedisease. In certain embodiments the method provides a beneficial effectby lessening the discomfort associated with a disorder.

As used herein, the term “therapeutically effective amount” or“effective amount” refers to that amount of a therapeutic agentsufficient to result in the amelioration of one or more symptoms of adisorder, prevent advancement of a disorder, cause regression of adisorder, prevent the recurrence of a disorder, or enhance or improvethe prophylactic or therapeutic effect(s) of another modality, or lessenthe discomfort associated with a disorder. The following parameters canbe used to evaluate the disease course and effects of therapy includingbut not limited to subjective nasal clinical symptoms (nasal discharge,nasal obstruction, postnasal drip and headache), X-ray photographs(either full or limited computerized axial tomograms (CT) scans and/ormagnetic resonance imaging (MRI) or the sinuses, and cytokine levels(e.g., IL-1 beta, IL-8 and TNF-alpha) by enzyme-linked immunosorbentassays appropriate for the mammal being evaluated and treated.

As used herein, the terms “therapeutic agent” and “therapeutic agents”refer to any agent such as e.g., a proinflammatory cytokine antagonis,which can be used in the treatment, management, or amelioration of adisorder, or one or more symptoms thereof. In certain embodiments, theterm “therapeutic agent” refers to a compound or composition of theinvention. Therapeutic agents may be characterized as different agentsbased upon one or more effects the agents have in vivo and/or in vitro,for example, an anti-inflammatory agent may also be characterized as animmunomodulatory agent.

As used herein, the terms “prophylactic agent” and “prophylactic agents”as used refer to any agent(s) that can be used in the prevention of adisorder or one or more symptoms thereof. In certain embodiments, theterm “prophylactic agent” refers to a compound or composition of theinvention. Prophylactic agents may be characterized as different agentsbased upon one or more effects that the agents have in vitro and/or invivo.

As used herein, the phrase “prophylactically effective amount” refers tothe amount of a prophylactic agent that is sufficient to result in theprevention or inhibition of the development, recurrence, or onset of adisorder or a symptom thereof, or to enhance or improve the prophylacticeffect(s) of another modality (e.g., another prophylactic agent).Certain examples of prophylactically effective amounts of compounds orcompositions are provided infra.

In another embodiment, with respect to inflammation, an effective amountrefers to the amount of a therapy (e.g., a therapeutic agent) thatreduces the inflammation of the upper airways or a region of the upperairways (e.g., sinus, sinuses, nasal lining). Preferably, atherapeutically effective of a therapy (e.g., a therapeutic agent)reduces the inflammation by at least 5%, preferably at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 99%, relative to a control orplacebo such as phosphate buffered saline. Examples of therapeuticallyeffective amounts of compounds are provided infra.

The invention also provides methods for the prevention, treatment,management, or amelioration of proliferative disorders or inflammatorydisorders, or one or more symptoms thereof, said methods comprisingadministering to a subject in need thereof a prophylactically ortherapeutically effective amount of one or more compounds or acomposition of the invention and a prophylactically or therapeuticallyeffective amount of at least one other modality (e.g., at least oneother prophylactic or therapeutic agent) other than a compound of theinvention.

As used herein, the term “in combination” or “co-administration” refersto the use of more than one modalities (e.g., one or more prophylacticand/or therapeutic agents). The use of the term “in combination” or“co-administration” does not restrict the order in which modalities areadministered to a subject with rhinosinusitis. A first modality (e.g., aprophylactic or therapeutic agent such as a compound of the invention)can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes,45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequentto (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or12 weeks after) the administration of a second modality (e.g., aprophylactic or therapeutic agent such as an anti-inflammatory agent oranti-angiogenic agent) to a subject with rhinosinusitis.

As used herein, the term “synergistic” refers to a combination ofcompounds of the invention and/or a combination of a compound, compoundsor a composition of the invention and another modality (e.g., aprophylactic or therapeutic agent), including one which has been or iscurrently being used to prevent, manage or treat a disorder, whichcombination is more effective than the additive effects of theindividual compounds or therapies. A synergistic effect of a combinationof modalities (e.g., a combination of prophylactic or therapeuticagents) can permit the use of lower dosages of one or more of themodalities and/or less frequent administration of said modalities to asubject with a disorder. The ability to utilize lower dosages ofprophylactic or therapeutic agent and/or to administer said agent lessfrequently can reduce the toxicity associated with the administration ofsaid agent to a subject without reducing the efficacy of said agent inthe prevention, management, or treatment of a disorder. In addition, asynergistic effect can result in improved efficacy of agents in theprevention, management, or treatment of a disorder. Moreover, asynergistic effect of a combination of prophylactic or therapeuticagents can avoid or reduce adverse or unwanted side effects associatedwith the use of either therapy alone.

As used herein, the phrase “side effects” encompasses unwanted andadverse effects of a modality. Side effects are always unwanted, butunwanted effects are not necessarily adverse. An adverse effect might beharmful, uncomfortable or risky. Side effects include, but are notlimited to sinus congestions, pain, fever, chills, lethargy,gastrointestinal toxicities (including gastric and intestinalulcerations and erosions), nausea, vomiting, neurotoxicities,nephrotoxicities, renal toxicities (including such conditions aspapillary necrosis and chronic interstitial nephritis), hepatictoxicities (including elevated serum liver enzyme levels),myelotoxicities (including leukopenia, myelosuppression,thrombocytopenia and anemia), dry mouth, metallic taste, prolongation ofgestation, weakness, somnolence, pain (including muscle pain, bone painand headache), hair loss, asthenia, dizziness, extra pyramidal symptoms,akathisia, cardiovascular disturbances and sexual dysfunction.

One or more compounds and/or compositions of the invention can be usedto prevent, treat, manage, or ameliorate a proliferative disorder or oneor more symptoms thereof. The present invention provides methods forpreventing, treating, managing, or ameliorating one or more symptoms ofa non-cancerous disorder associated with cellular hyperproliferation,particularly of epithelial cells (e.g., as in upper airways diseaseincluding polyps, sinusitis, and nasal obstruction), said methodscomprising administering to a subject in need thereof one or morecompounds of the invention. The present invention also provides methodsfor preventing, managing, treating, or ameliorating a non-cancerousdisorder of the upper airways associated with cellularhyperproliferation including polyps, said methods comprising ofadministering to a subject in need thereof one or more compounds orcompositions of the invention and one or more other therapies (e.g., oneor more other prophylactic or therapeutic agents) useful for theprevention, treatment, management, or amelioration of said disorder.

In a specific embodiment, the invention provides methods for preventing,managing, treating, or ameliorating polyps or other non-cancerousdisorder associated with cellular hyperproliferation, said methodscomprising of administering to a subject in need thereof aprophylactically or therapeutically effective amount of one or morecompounds of the invention. In another embodiment, the inventionprovides methods for preventing, managing, treating, or ameliorating apolyps and other non-cancerous disorder associated with cellularhyperproliferation or one or more symptoms thereof, said methodscomprising of administering to a subject in need thereof aprophylactically or therapeutically effective amount of one or marecompounds of the invention and a prophylactically or therapeuticallyeffective amount of one or more other therapies (e.g., one or moreprophylactic or therapeutic agents).

The invention encompasses methods for preventing, treating, managing, orameliorating one or more symptoms of a disorder associated with cellularhyperproliferation including polyps in a subject refractory toconventional therapies for such disorder, said methods comprisingcontacting with or administering to subject a dose of a prophylacticallyor therapeutically effective amount of one or more compounds of theinvention. The present invention also provides methods for preventing,managing, treating, or ameliorating a non-cancerous disorder associatedwith cellular hyperproliferation in a subject refractory to conventionaltherapies for such disorder, said methods comprising of administering toa subject in need thereof one or more compounds of the invention and oneor more other therapies (e.g., one or more other prophylactic ortherapeutic agents) useful for the prevention, treatment, management, oramelioration of said disorder.

In a specific embodiment, the invention provides a method of preventingor treating a disorder, e.g., rhinosinusitis, or symptom thereofcomprising administering to a subject in need thereof a dose of at least100 micrograms, preferably at least 250 micrograms, at least 500micrograms, at least 1000 micrograms, at least 5000 micrograms, or moreof one or more compounds of the invention once every 3 days, preferably,once every 4 days, once every 5 days, once every 6 days, once every 7days, once every 8 days, once every 10 days, once every two weeks, onceevery three weeks, or once a month.

In a preferred embodiment of the invention, methods for treating upperairways disease are provided. In the methods, a composition isadministered to a mammal diagnosed as hay upper airways disease. Themethods of the invention can be employed in combination with still othertherapeutic techniques such as endoscopic monitoring and treatmenttechniques, sinus drainage and polyp removal.

The method and instruments of the invention, used separately ortogether, can be employed to treat a variety of conditions and targetsites, including sino-nasal target sites. Exemplary target sites includeeither or both nostrils, the left or right lower nasal cavity, the leftor right upper nasal cavity, the sinuses, especially those sinuses thatare accessible via the nasal cavity and, if accessible, the frontal,ethmoidal, sphenoidal and maxillary sinuses.

The above-described devices and methods of delivery of bioactivematerials, preferably one or more therapeutic agent(s), provide a numberof unexpected advantages over the existing treatments relying onaerosols or nasal sprays and the associated devices and methods to treatnasal disease including rhinitis and sinusitis. The advantages include,but are not limited to, the simple and economical, yet reliable,operation of the devices, that improve the distribution of materialsincluding therapeutics to the nasal region including the paranasalsinuses.

Inflammatory Disorders

One or more pro-inflammatory cytokine inhibitor of the invention can beused to prevent, treat, manage, relieve, or ameliorate an inflammatorydisorder or one or more symptoms thereof. The compounds of the inventionor compositions comprising said compounds may also be administered incombination with one or more other therapies (e.g., one or more otherprophylactic or therapeutic agents) useful for the prevention,treatment, management, or amelioration of a condition associated withinflammation (in particular, an inflammatory disorder) or one or moresymptoms thereof.

The compounds or compositions of the invention can be used to prevent,reduce, or eliminate one or more symptoms and/or conditions associatedwith inflammation, for examples, redness, excess warmth, edema(swelling), and/or pain associated with inflammation can be prevented,reduced or eliminated.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating an upper airways disease associatedwith inflammation or one or more symptoms thereof, said methodcomprising contacting with or administering to a subject in need thereofa dose of a prophylactically or therapeutically effective amount one ormore compounds of the invention. Another embodiment of the invention isa method of preventing, treating managing, or ameliorating a conditionassociated with inflammation (e.g., an inflammatory disorder) or one ormore symptoms thereof, said method comprising administering to a subjectin need thereof a dose of a prophylactically or therapeuticallyeffective amount of one or more of compounds of the invention and a doseof a prophylactically or therapeutically effective amount of one or moreother therapies (e.g., one or more other prophylactic or therapeuticagents).

The invention also provides methods for preventing, managing, treatingor ameliorating an upper airways disease or one or more symptoms thereofin a subject refractory to conventional therapies (e.g., steroids,non-steroidal anti-inflammatory compounds, anti-cholinergics,anti-histamines and decongestants) for said condition, said methodscomprising administering to said subject a dose of a prophylactically ortherapeutically effective amount of one or more compounds of theinvention. The invention also provides methods for preventing, treating,managing, or ameliorating an upper airways disease or one or moresymptoms thereof in a subject refractory to existing single agenttherapies for such a condition, said methods comprising administering tosaid subject a dose of a prophylactically or therapeutically effectiveamount of one or more compounds of the invention and a dose of aprophylactically or therapeutically effective amount of one or moreother therapies (e.g., one or more other prophylactic or therapeuticagents). The invention also provides methods for administering one ormore compounds of the invention in combination with any othertherapy(ies) to patients who have proven refractory to other treatmentsbut are no longer on this therapy(ies). The invention also providesalternative methods for the prevention, treatment, management, oramelioration of an upper airways disease where another therapy hasproven or may prove too toxic, i.e., results in unacceptable orunbearable side effects, for the subject being treated. Further, theinvention provides methods for preventing the recurrent upper airwaydisease in patients that have been treated and have no disease activityby administering one or more compounds of the invention.

In a specific embodiment, an effective amount of one or more compoundsof the invention is administered to a subject in combination with aneffective amount of one or more therapies (e.g., prophylactic ortherapeutic agents) useful in preventing, treating, managing, orameliorating sinus congestion and one or more symptoms thereof. Examplesof such therapies include, but are not limited to, adrenergic stimulants(e.g., catecholamines (e.g., epinephrine, isoproterenol, andisoetharine)), resorcinols (e.g., metaproterenol, terbutaline, andfenoterol), saligenins (e.g., salbutamol), anticholinergics (e.g.,atropine sulfate, atropine methylnitrate, and ipratropium bromide(ATROVENT)), beta2-agonists (e.g., albuterol (VENTOLIN and PROVENTIL),bitolterol (TORNALATE), levalbuterol (XOPONEX), metaproterenol(ALUPENT), pirbuterol (MAXAIR), terbutlaine (BRETHAIRE and BRETHINE),albuterol (PROVENTIL, REPETABS, and VOLMAX), formoterol (FORADILAEROLIZER), and salmeterol (SEREVENT and SEREVENT DISKUS),corticosteroids (e.g., methylprednisolone (MEDROL)), prednisone(PREDNISONE and DELTASONE), and prednisolone (PRELONE, PEDIAPRED),glucocorticoids (e.g., oral steroids or other systemic or oral steroids,and inhaled gucocoritcoids), other steroids, immunosuppressant agents(e.g., methotrexate and gold salts), leukotriene modifiers (e.g.,montelukast (SINGULAIR), zafirlukast (ACCOLATE), and zileuton (ZYFLO)),mast cell stabilizers (e.g., cromolyn sodium (INTAL) and nedocromilsodium (TILADE), methylxanthines (e.g., theophylline (UNIPHYL, THEO-DUR,SLO-BID, and TEHO-42)), and mucolytic agents (e.g., acetylcysteine,pulmozyme or dornase alpha (rhDNase) (Genentech)).

In a specific embodiment, an effective amount of a proinflammatorycytokine inhibitor of the invention is administered to the upper airwaysof a subject in need of such treatment in combination with an effectiveamount of one or more therapies (e.g., prophylactic or therapeuticagents) useful in preventing, treating, managing, or ameliorating one ormore symptoms of a disorder. Non-limiting examples of therapies includeantimediator drugs including but not limited to antihistamines,corticosteroids, decongestants, sympathomimetic drugs (e.g.,alpha-adrenergic and beta-adrenergic drugs), theophylline and itsderivatives, glucocorticoids, and immunotherapies.

In a specific embodiment, an effective amount of a proinflammatorycytokine inhibitor and one or more compounds of the invention areadministered to the upper airways of a subject in combination with aneffective amount of one or more therapies (e.g., prophylactic ortherapeutic agents) useful in preventing, treating, managing, orameliorating rhinosinusitis due to various etiologic agents.Non-limiting examples of such therapies include, but are not limited to,exogenous alphalanti trypsin or other serine protease inhibitors, yearlyinfluenza vaccine or pneumococcal vaccination.

Infectious Diseases

One or more pro-inflammatory cytokine inhibitor can be used to prevent,treat, manage, relieve, or ameliorate an infectious disease or one ormore symptoms thereof. The compounds or compositions of the inventioncan also be administered in combination with one or more other therapies(e.g., one or more other prophylactic or therapeutic agents) useful forthe prevention, treatment, management, or amelioration of a conditionassociated with an infectious disease or one or more symptoms thereof.

Infectious viruses of mammals and both human and non-human vertebrates,include bacterial, atypical bacteria, retroviruses, RNA viruses and DNAviruses. Examples of virus that have been found in humans include butare not limited to: Retroviridae (e.g., human immunodeficiency viruses,such as HIV-1 (also referred to as HTLV-III, LAV or HTLV-II/LAV, orHIV-III; and other isolates, such as HIV-LP; Picomaviridae (e.g., polioviruses, hepatitis A virus; enteroviruses, human Coxsackie viruses,rhinoviruses, echoviruses); Calciviridae (e.g., strains that causegastroenteritis); Togaviridae (e.g., equine encephalitis viruses,rubella viruses); Flaviridae (e.g. dengue viruses, encephalitis viruses,yellow fever viruses); Coronaviridae (e.g., coronaviruses);Rhabdoviridae (e.g., vesicular stomatitis viruses, rabies viruses);Filoviridae (e.g., ebola viruses); Paramyxoviridae (e.g., parainfluenzaviruses, mumps virus, measles virus, respiratory syncytial virus);Orthomyxoviridae (e.g., influenza viruses); Bungaviridae (e.g., Hantaanviruses, bunga viruses, phleboviruses and Nairo viruses); Arena viridae(hemorrhagic fever viruses); Reoviridae (e.g., reoviruses, orbiviursesand rotaviruses); Bimaviridae; Hepadnaviridae (Hepatitis B virus);Parvovirida (parvoviruses); Papovaviridae (papilloma viruses, polyomaviruses); Adenoviridae (most adenoviruses); Herpesviridae (herpessimplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus(CMV), herpes virus; Poxviridae (variola viruses, vaccinia viruses, poxviruses); and Iridoviridae (e.g. African swine fever virus); andunclassified viruses (e.g., the etiological agents of Spongiformencephalopathies, the agent of delta hepatitis (thought to be adefective satellite of hepatitis B virus), the agents of non-A, non-Bhepatitis (class 1=internally transmitted; class 2=parenterallytransmitted (i.e., Hepatitis C); Norwalk and related viruses, andastroviruses).

Retroviruses that are contemplated include both simple retroviruses andcomplex retroviruses. The simple retroviruses include the subgroups ofB-type retroviruses, C-type retroviruses and D-type retroviruses. Anexample of a B-type retrovirus is mouse mammary tumor virus (MMTV). TheC-type retroviruses include subgroups C-type group A (including Roussarcoma virus (RSV), avian leukemia virus (ALV), and avianmyeloblastosis virus (AMV) and C-type group B (including murine leukemiavirus (MLV), feline leukemia virus (FeLV), murine sarcoma virus (MSV),gibbon ape leukemia virus (GALV), spleen necrosis virus (SNV),reticuloendotheliosis virus (RV) and simian sarcoma virus (SSV). TheD-type retroviruses include Mason-Pfizer monkey virus (MPMV) and simianretrovirus type 1 (SRV-1). The complex retroviruses include thesubgroups of lentiviruses, T-cell leukemia viruses and the foamyviruses. Lentiviruses include HIV-1, but also include HIV-2, SIV, Visnavirus, feline immunodeficiency virus (FIV), and equine infectious anemiavirus (EIAV). The T-cell leukemia viruses include HTLV-1, HTLV-11,simian T-cell leukemia virus (STLV), and bovine leukemia virus (BLV).The foamy viruses include human foamy virus (HFV), simian foamy virus(SFV) and bovine foamy virus (BFV).

Examples of RNA viruses that are antigens in vertebrate animals include,but are not limited to, the following: members of the family Reoviridae,including the genus Orthoreovirus (multiple serotypes of both mammalianand avian retroviruses), the genus Orbivirus (Bluetongue virus,Eugenangee virus, Kemerovo virus, African horse sickness virus, andColorado Tick Fever virus), the genus Rotavirus (human rotavirus,Nebraska calf diarrhea virus, murine rotavirus, simian rotavirus, bovineor ovine rotavirus, avian rotavirus); the family Picomaviridae,including the genus Enterovirus (poliovirus, Coxsackie virus A and B,enteric cytopathic human orphan (ECHO) viruses, hepatitis A virus,Simian enteroviruses, Murine encephalomyelitis (ME) viruses, Poliovirusmuris, Bovine enteroviruses, Porcine enteroviruses, the genusCardiovirus Encephalomyocarditis virus (EMC), Mengovirus), the genusRhinovirus (Human rhinoviruses including at least 113 subtypes; otherrhinoviruses), the genus Apthovirus (Foot and Mouth disease (FMDV); thefamily Caleiviridae, including Vesicular exanthema of swine virus, SanMiguel sea lion virus, Feline picornavirus and Norwalk virus; the familyTogaviridae, including the genus Alphavirus (Eastern equine encephalitisvirus, Semliki forest virus, Sindbis virus, Chikungunya virus,O'Nyong-Nyong virus, Ross river virus, Venezuelan equine encephalitisvirus, Western equine encephalitis virus), the genus Flavirius (Mosquitoborne yellow fever virus, Dengue virus, Japanese encephalitis virus, St.Louis encephalitis virus, Murray Valley encephalitis virus, West Nilevirus, Kunjin virus, Central European tick borne virus, Far Eastern tickborne virus, Kyasanur forest virus, Louping III virus, Powassan virus,Omsk hemorrhagic fever virus), the genus Rubivirus (Rubella virus), thegenus Pestivirus (Mucosal disease virus, Hog cholera virus, Borderdisease virus); the family Bunyaviridae, including the genus Bunyvirus(Bunyarnwera and related viruses, California encephalitis groupviruses), the genus Phlebovirus (Sandfly fever Sicilian virus, RiftValley fever virus), the genus Nairovirus (Crimean-Congo hemorrhagicfever virus, Nairobi sheep disease virus), and the genus Uukuvirus(Uukuniemi and related viruses); the family Orthomyxoviridae, includingthe genus Influenza virus (Influenza virus type A, many human subtypes);Swine influenza virus, and Avian and Equine Influenza viruses; influenzatype B (many human subtypes), and influenza type C (possible separategenus); the family paramyxoviridae, including the genus Paramyxovirus(Parainfluenza virus type 1, Sendai virus, Hemadsorption virus,Parainfluenza viruses types 2 to 5, Newcastle Disease Virus, Mumpsvirus), the genus Morbillivirus (Measles virus, subacute sclerosingpanencephalitis virus, distemper virus, Rinderpest virus), the genusPneumovirus (respiratory syncytial virus (RSV), Bovine respiratorysyncytial virus and Pneumonia virus of mice); forest virus, Sindbisvirus, Chikungunya virus, O'Nyong-Nyong virus, Ross river virus,Venezuelan equine encephalitis virus, Western equine encephalitisvirus), the genus Flavirius (Mosquito borne yellow fever virus, Denguevirus, Japanese encephalitis virus, St. Louis encephalitis virus, MurrayValley encephalitis virus, West Nile virus, Kunjin virus, CentralEuropean tick borne virus, Far Eastern tick borne virus, Kyasanur forestvirus, Louping III virus, Powassan virus, Omsk hemorrhagic fever virus),the genus Rubivirus (Rubella virus), the genus Pestivirus (Mucosaldisease virus, Hog cholera virus, Border disease virus); the familyBunyaviridae, including the genus Bunyvirus (Bunyarnwera and relatedviruses, California encephalitis group viruses), the genus Phlebovirus(Sandfly fever Sicilian virus, Rift Valley fever, virus), the genusNairovirus (Crimean-Congo hemorrhagic fever virus, Nairobi sheep diseasevirus), and the genus Uukuvirus (Uukuniemi and related viruses); thefamily Orthomyxoviridae, including the genus Influenza virus (Influenzavirus type A, many human subtypes); Swine influenza virus, and Avian andEquine Influenza viruses; influenza type B (many human subtypes), andinfluenza type C (possible separate genus); the family paramyxoviridae,including the genus Paramyxovirus (Parainfluenza virus type 1, Sendaivirus, Hemadsorption virus, Parainfluenza viruses types 2 to 5,Newcastle Disease Virus, Mumps virus), the genus Morbillivirus (Measlesvirus, subacute sclerosing panencephalitis virus, distemper virus,Rinderpest virus), the genus Pneumovirus (respiratory syncytial virus(RSV), Bovine respiratory syncytial virus and Pneumonia virus of mice);the family Rhabdoviridae, including the genus Vesiculovirus (VSV),Chandipura virus, Flanders-Hart Park virus), the genus Lyssavirus(Rabies virus), fish Rhabdoviruses, and two probable Rhabdoviruses(Marburg virus and Ebola virus); the family Arenaviridae, includingLymphocytic choriomeningitis virus (LCM), Tacaribe virus complex, andLassa virus; the family Coronaviridae, including infectious BronchitisVirus (IBV), Mouse Hepatitis virus, Human enteric corona virus, andFeline infectious peritonitis (Feline coronavirus).

Illustrative DNA viruses that are antigens in vertebrate animalsinclude, but are not limited to: the family Poxviridae, including thegenus Orthopoxvirus (Variola major, Variola minor, Monkey pox Vaccinia,Cowpox, Buffalopox, Rabbitpox, Ectromelia), the genus Leporipoxvirus(Myxoma, Fibroma), the genus Avipoxvirus (Fowlpox, other avianpoxvirus), the genus Capripoxvirus (sheeppox, goatpox), the genusSuipoxvirus (Swinepox), the genus Parapoxvirus (contagious postulardermatitis virus, pseudocowpox, bovine papular stomatitis virus); thefamily Iridoviridae (African swine fever virus, Frog viruses 2 and 3,Lymphocystis virus of fish); the family Herpesviridae, including thealpha-Herpesviruses (Herpes Simplex Types 1 and 2, Varicella-Zoster,Equine abortion virus, Equine herpes virus 2 and 3, pseudorabies virus,infectious bovine keratoconjunctivitis virus, infectious bovinerhinotracheitis virus, feline rhinotracheitis virus, infectiouslaryngotracheitis virus) the Beta-herpesviruses (Human cytomegalovirusand cytomegaloviruses of swine, monkeys and rodents); thegamma-herpesviruses (Epstein-Barr virus (EBV), Marek's disease virus,Herpes saimiri, Herpesvirus ateles, Herpesvirus sylvilagus, guinea pigherpes virus, Lucke tumor virus); the family Adenoviridae, including thegenus Mastadenovirus (Human subgroups A, B, C, D, E and ungrouped;simian adenoviruses (at least 23 serotypes), infectious caninehepatitis, and adenoviruses of cattle, pigs, sheep, frogs and many otherspecies, the genus Aviadenovirus (Avian adenoviruses); andnon-cultivatable adenoviruses; the family Papoviridae, including thegenus Papiliornavirus (Human papilloma viruses, bovine papillomaviruses, Shope rabbit papilloma virus, and various pathogenic papillomaviruses of other species), the genus Polyomavirus (polyomavirus, Simianvacuolating agent (SV-40), Rabbit vacuolating agent (RKV), K virus, BKvirus, JC virus, and other primate polyoma viruses such as Lymphotrophicpapilloma virus); the family Parvoviridae including the genusAdeno-associated viruses, the genus Parvovirus (Feline panleukopeniavirus, bovine parvovirus, canine parvovirus, Aleutian mink diseasevirus, etc). Finally, DNA viruses may include viruses that do not fitinto the above families such as Kura and Creutzfeldt-Jacob diseaseviruses and chronic infectious neuropathic agents.

Bacterial infections or diseases that can be treated or prevented by themethods of the present invention are caused by bacteria including, butnot limited to, bacteria that have an intracellular stage in its lifecycle, such as mycobacteria (e.g., Mycobacteria tuberculosis, M. bovis,M. avium, M. leprae, or M. africanum), rickettsia, mycoplasma,chlamydia, and legionella. Other examples of bacterial infectionscontemplated include but are not limited to infections caused by Grampositive bacillus (e.g., Listeria, Bacillus such as Bacillus anthracts,Erysipelothrix species), Gram negative bacillus (e.g., Bartonella,Brucella, Campylobacter, Enterobacter, Escherichia, Francisella,Hemophilus, Klebsiella, Morganella, Proteus, Providencia, Pseudomonas,Salmonella, Serratia, Shigella, Vibrio, and Yersinia species),spirochete bacteria (e.g., Borrelia species including Borreliaburgdorferi that causes Lyme disease), anaerobic bacteria (e.g.,Actinomyces and Clostridium species), Gram positive and negative coccalbacteria, Enterococcus species, Streptococcus species, Pneumococcusspecies, Staphylococcus species, Neisseria species. Specific examples ofinfectious bacteria include but are not limited to: Helicobacterpyloris, Borelia burgdorferi, Legionella pneumophilia, Mycobacteriatuberculosis, M. avium, M. intracellulare, M. karma, M. gordonae,Staphylococcus aureus, Neisseria gonorrhoeae, Neisseria meningitidis,Listeria monocytogenes, Streptococcus pyogenes (Group A Streptococcus),Streptococcus agalactiae (Group B Streptococcus), Streptococcusviridans, Streptococcus faecalis, Streptococcus bovis, Streptococcuspneumoniae, Haemophilus influenzae, Bacillus antracis, corynebacteriumdiphtheriae, Erysipelothrix rhusiopathiae, Clostridium perfringers,Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae,Pasturella multocida, Fusobacterium nucleatum, Streptobacillusmontliformis, Treponema palladium, Treponema pertenue, Leptospira,Rickettsia, and Actinomyces Israeli.

Fungal Disease

Fungal infections or conditions resulting from or associated with afungal infection (e.g., rhinosinusitis) can be prevented, treated,managed, and/or ameliorated in accordance with the methods of invention.Examples of fungus which cause fungal infections include, but notlimited to, Absidia species (e.g., Absidia corymbifera and Absidiaramosa), Aspergillus species, (e.g., Aspergillus flavus,Aspergillusfumigatus, Aspergillus nidulans, Aspergillus niger, andAspergillus terreus), Basidiobolus ranarum, Blastomyces dermatitidis,Candida species (e.g., Candida albicans, Candida glabrata, Candida kerr,Candida krusei, Candida parapsilosis, Candida pseudotropicalis, Candidaquillermandii, Candida rugosa, Candida stellatoidea, and Candidatropicalis), Coccidioides immitis, Conidiobolus species, Cryptococcusneoforms, Cunninghamella species, dermatophytes, Histoplasma capsulatum,Microsporum gypseum, Mucor pusillus, Paracoccidioides brasiliensis,Pseudallescheria boydii, Rhinasporidium seeberi, Pneumocystis carinii,Rhizopus species (e.g., Rhizopus arrhizus, Rhizopus oryzae, and Rhizopusmicrosporus), Saccharomyces species, Sporothrix schenckil, zygomycetes,and classes such as Zygomycetes, Ascomycetes, the Basidiomycetes,Deuteromycetes, and Oomycetes. In addition, fungal diseases that can betreated or prevented by the methods of the present invention include butnot limited to aspergilliosis, crytococcosis, sporotrichosis,coccidioidomycosis, paracoccidioidomycosis, histoplasmosis,blastomycosis, zygomycosis, and candidiasis.

Parasitic Disease

Parasitic diseases that can be treated or prevented by the methods ofthe present invention including, but not limited to, amebiasis, malaria,leishmania, coccidia, giardiasis, cryptosporidiosis, toxoplasmosis, andtrypanosomiasis. Also encompassed are infections by various worms, suchas but not limited to ascariasis, ancylostomiasis, trichuriasis,strongyloidiasis, toxoccariasis, trichinosis, onchocerciasis, filaria,and dirofilariasis. Also encompassed are infections by various flukes,such as but not limited to schistosomiasis, paragonimiasis, andclonorchiasis. Parasites that cause these diseases can be classifiedbased on whether they are intracellular or extracellular. An“intracellular parasite” as used herein is a parasite whose entire lifecycle is intracellular. Examples of human intracellular parasitesinclude Leishmania species, Plasmodium species, Trypanosorna cruzi,Toxoplasma gondii, Babesia species, and Trichinella spiralis. An“extracellular parasite” as used herein is a parasite whose entire lifecycle is extracellular. Extracellular parasites capable of infectinghumans include Entamoeba histolytica, Giardia lamblia, Enterocytozoonbieneusi, Naegleria and Acanthamoeba as well as most helminths. Yetanother class of parasites is defined as being mainly extracellular butwith an obligate intracellular existence at a critical stage in theirlife cycles. Such parasites are referred to herein as “Obligateintracellular parasites”. These parasites may exist most of their livesor only a small portion of their lives in an extracellular environment,but they all have at least one obligate intracellular stage in theirlife cycles. This latter category of parasites includes Trypanosomarhodesiense and Trypanosoma gambiense, Isospora, Cryptosporidium,Eimeria, Neospora, Sarcocystis, and Schistosoma.

Biological Assays

Another aspect of the invention is a bioassay for determining theefficiency of a proinflammatory cytokine antagonist in the treatment ofa disorder. Aspects of the pharmaceutical compositions or compounds ofthe invention can routinely be tested in vitro, in a cell culturesystem, and/or in an animal model organism, such as a rodent animalmodel system, for a desired activity prior to use in humans. Forexample, assays can include cell culture assays in which a tissue sampleis grown in culture, and exposed to or otherwise contacted with apharmaceutical composition, and the effect of such composition upon thetissue sample is observed. The tissue sample, for example, can beobtained by collection from a subject. This test allows theidentification of the therapeutically most effective therapy (e.g.,prophylactic or therapeutic agent(s)) for each individual patient. Invarious specific embodiments, in vitro assays can be carried out withrepresentative cells of cell types involved in a disorder (e.g.,epithelial cells, immune cells, or polyps), to determine if a compoundor composition of the invention has a desired effect upon such celltypes. As an alternative to the use of tissue, tissue samples, or celllines, e.g., cancer cell lines can be used in in vitro assays.

The pharmaceutical compositions and compounds of the invention can alsobe assayed for their ability to induce or inhibit the expression and/oractivation of a gone product (e.g., cellular protein or RNA) and/or toinduce signal transduction in immune cells, cancer cells, and/orendothelial cells. The induction of the expression or activation of agene product or the induction of signal transduction pathways in immunecells and/or epithelial cells can be assayed by techniques known tothose of skill in the art including, e.g., ELISAs flow cytometry,northern blot analysis, western blot analysis, RT-PCR kinase assays andelectrophoretic mobility shill assays. The compositions and compounds ofthe invention can also be assayed for their ability to modulate cellproliferation including immune cells using the example, techniques knownto those in art, including, but not limited to, tritiated thymidineincorporation, trypan blue cell counts, and fluorescence activated cellsorting (“FACS”) analysis. The compositions and compounds of theinvention can also be assayed for their ability to induce cytolysis. Thecompositions and compounds of the invention can also be assayed fortheir ability to inhibit cell migration cell adhesion and angiogenesisusing techniques well-known to one of skill in the art or asincorporated or described herein.

The pharmaceutical compositions and compounds of the invention can alsobe tested in suitable animal model systems prior to use in humans. Anyanimal system well known in the art may be used. In a specificembodiment of the invention, the pharmaceutical compositions andcompounds of the invention are tested in a mouse model system. In apreferred embodiment, the mouse is a transgenic animal with a geneticpredisposition to environmentally induced upper airways disorders. Suchanimal model systems include, but are not limited to, rats, mice,chicken, cows, monkeys, pigs, dogs, rabbits, etc. Such model systems arewidely used and well known to the skilled artisan.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage of the pharmaceutical compositionsand compounds of the invention for use in humans. The dosage of suchagents lies preferably within a range with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the method of administration utilized. For any agent usedin the methods of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose may be confirmedin animal models. Such information can be used to more accuratelydetermine useful doses in humans. Levels in plasma may be measured forsystemic absorption, for example, by high performance liquidchromatography (HPLC) and radioimmunasssay (RIA).

Efficacy in preventing or treating a proliferative disorder such aspolyps may be demonstrated, e.g., by detecting the ability of thepharmaceutical compositions and compounds of the invention to reduce oneor more symptoms of the proliferative disorder, to reduce the numbers ofproliferating cells, to reduce the spread of inflammatory cells, or toreduce the size of a polyp, as for example, by using techniques andmethods described herein.

The following working examples specifically point out preferredembodiments of the present invention, and are not to be construed aslimiting in any way the remainder of the disclosure. Other genericconfigurations will be apparent to one skilled in the art.

EXAMPLES Example 1 Spray Content Uniformity

This test is designed to demonstrate the uniformity of medication perspray (or minimum dose), consistent with the label claim, to bedischarged from the nasal actuator, of an appropriate number (n=about 10from beginning and n=about 10 from end) of containers from a batch. Theprimary purpose is to ensure spray content uniformity within the samecontainer and among multiple containers of a batch.

Techniques for thoroughly analyzing the spray discharged from the nasalactuator for the drug substance content include multiple sprays frombeginning to the end of an individual container, among. Containers, andamong batches of drug product. This test provides an overall performanceevaluation of a batch, assessing the formulation, the manufacturingprocess, and the pump. At most, two sprays per determination are usedexcept in the case where the number of sprays per minimum dose specifiedin the product labeling is one. To ensure reproducible in vitro dosecollection, the procedure will have controls for actuation parameters(e.g., stroke length, actuation force). The test is performed with unitsprimed following the instructions in the labeling. The amount of drugsubstance delivered from the nasal actuator is expressed both as theactual amount and as a percentage of label claim.

The following acceptance criteria are used. However, alternativeapproaches (e.g., statistical) may be used to provide equal or greaterassurance of spray content uniformity. In general, for acceptance of abatch (1) the amount of active ingredient per determination is notoutside of 80 to 120 percent of label claim for mere than 2 of 20determinations (10 from beginning and 10 from end) from 10 containers,(2) none of the determinations is outside of 75 to 125 percent of thelabel claim, and (3) the mean for each of the beginning and enddeterminations are not outside of 85 to 115 percent of label claim.

If the above acceptance criteria are not met because 3 to 6 of the 20determinations are outside of 80 to 120 percent of the label claim, butnone are outside of 75 to 125 percent of label claim and the means foreach of the beginning and end determinations are not outside of 85 to115 percent of label claim, an additional 20 containers will be sampledfor second-tier testing. For the second tier of testing of a batch, theacceptance criteria are met if (1) the amount of active ingredient perdetermination is not outside of 80 to 120 percent of the label claim formore than 6 of all 60 determinations, (2) none of the 60 determinationsis outside of 75 to 125 percent of label claim, and (3) the means foreach of the beginning and end determinations are not outside of 85 to115 percent of label claim

Example 2 Testing Droplet Size Distribution

When testing droplet size distribution for both suspension and solutionnasal sprays, an appropriate control for droplet size distribution isimportant (e.g., 3 to 4 cut-off values) of the delivered plumesubsequent to spraying under specified experimental and instrumentalconditions. In this example, a laser diffraction method is used, anddroplet size distribution is controlled in terms of ranges for the D₁₀,D₅₀, D₉₀, span ((D₉₀−D₁₀/D₅₀), and percentage of droplets less than 10micrometers is determined.

A multistage cascade impactor is used to fractionate and collectdroplets/particles of the composition formulation by aerodynamicdiameter through serial multistage impactions. Such a device with allassociated accessories allows determination of a size distributionthroughout the whole dose including, in particular, the smallparticle/droplet size fraction of the dose. It also provides informationthat allows the complete mass balance of the total labeled dose to bedetermined. To minimize distortions and to ensure reproducibility, theconditions are stipulated for a specific composition such as thecalibration of the equipment, flow rate, duration, size, and shape ofthe expansion chamber or inlet stern, and the procedure, accessories,and adapter that introduce the inhalation spray into a specifiedimpactor. These important parameters are determined to obtain a completeprofile of the dose. Before multiple cascade impactors of the samedesign are used, data will demonstrate comparability between impactorunits. The aerodynamic particle/droplet size distribution analysis andthe mass balance obtained (drug substance deposited on surfaces from theinlet to the cascade impactor filter) are used to determine thesuitability of the device with the composition. The total mass of drugcollected on all stages and accessories will be monitored on a givencomposition and a suitable device will deliver between 85 and 115percent of label claim on a per spray basis.

Example 3 Spray Pattern and Plume Geometry

The following testing is used to characterize spray pattern and plumegeometry when evaluating the performance of the pump. Various factorscan affect the spray pattern and plume geometry, including the size andshape of the nozzle, the design of the pump, the size of the meteringchamber, and the characteristics of the formulation. Spray patterntesting is performed on a routine basis as a quality control for releaseof the drug product. Characterization of plume geometry typically isestablished during the characterization of the product.

In the evaluation of the spray pattern, the spray distance between thenozzle and the collection surface, number of sprays per spray pattern,position and orientation of the collection surface relative to thenozzle, and visualization procedure are specified. The acceptancecriteria for spray pattern includes the shape (e g, ellipsoid ofrelative uniform density) as well as the size of the pattern (e.g., noaxis is greater than x millimeters and the ratio of the longest to theshortest axes should lie in a specified range). Data are generated todemonstrate that the collection distance selected for the spray patterntest provide the optimal discriminatory capability. Variability in thetest is controlled by the use of a product specific detection procedure.Plume geometry is evaluated by a variety of procedures (e.g., the timesequence sound-triggered high-speed flash photography method, videotaperecording and taking pictures of different frames), all well known iithe art. Photographs are of high quality. When monitoring the plumedevelopment and to define the shape two views, at 90 degrees to eachother and relative to the axis of the plume of the individual sprayplume are used.

Example 4 Test of Particle Size Distribution for Suspensions

For suspension nasal sprays, the specification includes tests andacceptance criteria for the particle size distribution of the drugsubstance particles in the formulation. The quantitative procedure isdetermined by the specific composition of the invention and validated,if feasible, in terms of its sensitivity and ability to detect shiftsthat may occur in the distribution. When examining formulations of thecomposition containing suspending agents in the presence of suspendeddrug substance, and the procedure cannot be acceptably validated, aqualitative and semiquantitative method for examination of drug andaggregated drug particle size distribution are used. For example,microscopic evaluation is used and such an examination provideinformation and data on the presence of large particles, changes inmorphology of the drug substance particles, extent of agglomerates, andcrystal growth.

Example 5 Test of Particulate Matter

Particulate matter may originate during manufacturing, from formulationcomponents, and from the container and closure components. Levels ofparticulate matter in the drug product can increase with time,temperature, and stress. If stability data generated in support of theapplication demonstrate that levels of particulate matter do notincrease with time, this testing of this attribute will occur duringbatch release. In general, the acceptance criteria will include, limitsfor foreign particulate matter less than 10 micrometers, greater than 10micrometers, and greater than 25 micrometers. For a description of thistest, refer to the USP.

Example 6 Test of Microbial Contaminants

The microbial quality is controlled by appropriate methods and checkedby microbial testing well known in the art. For a description of thistest, refer to the procedure in USP. Acceptance criteria for totalaerobic count, total yeast and mold count, and freedom from designatedindicator organisms are used. Testing will show that the drug productdoes not support the growth of microorganisms and that microbiologicalquality is maintained throughout the expiration dating period.

Example 7 Test of pH

For both solution and suspension nasal sprays, the pH or apparent pH, asappropriate, of the formulation are tested and an appropriate acceptancecriterion established. For a description of this test, refer to the USP.

Example 8 Test of Osmolality

For formulations containing an agent to control the tonicity or forproducts having a label claim regarding tonicity, the osmolality of theformulation should be tested and controlled at release with anappropriate procedure and acceptance criterion. For a description ofthis test, refer to the USP.

Example 9 Test of Viscosity

For formulations of the composition that contain an agent contributingto the viscosity, this parameter will be tested and controlled atrelease and on stability with an appropriate procedure and acceptancecriterion. For a description of this type of test, refer to the —USP.

Example 10 Assessment Therapeutic Effects

The following example illustrates methods for assessing the therapeuticeffects of a proinflammatory cytokine inhibitor (e.g., a TNF alphaantagonist) on nonallergic upper airways inflammation.

An exploratory multi-center, double blind, placebo-controlled,randomized, phase 2 trial is performed with 120 acute sinusitis patientswith mild-to-moderate symptoms who receive 14 days of an oral quinoloneantibiotic at the initiation of the study. Thirty patients also receivedaily intranasal inhalation of adalimumab (0.5 mg) for 28 days; anotherthirty patients receive daily intranasal inhalation of adalimumab (0.5mg) for 14 days following one subcutaneous injection of adalimumab (40mg) 14 days earlier (day 0) along with intranasal saline; another thirtypatients receive two subcutaneous injections of adalimumab (40 mg) onday 0 and day 14 with intranasal saline, and a fourth group of thirtypatients receive daily intranasal inhalation of saline daily from day 0through day 28.

Sinusitis is identified by history, clinical symptoms, and laboratoryfindings including abnormal CT scans, and validated questionnaire. Nasalfunction parameters and side effects were evaluated. Allergicpredisposition is assessed by skin-prick tests performed with a standardpanel of 10 or more common airborne allergens (ALK, Copenhagen, Denmark)including pollen, house dust mites, mold, and animal allergens. Allsubjects with a positive skin for at least one allergen are consideredallergic and separated from nonallergic subjects during study. Steroidsare withheld for a minimum of 6 weeks prior to and during the study. Allstudies are approved by the Institutional Review Board or EthicsCommittee as needed and an informed written consent is obtained fromeach subject.

Quantification of eosinophil and neutrophil numbers in nasal aspiratesare performed by counting numbers of human neutrophil elastase(HNE)-stained (for neutrophils) and EG2-stained (for eosinophils) cellsin a defined area of a defined volume of aspirate. Results are expressedas the average number of cells per volume of nasal lavage fluid

Quantification of cytokines is performed using commercially availableELISA methods as per the suppliers' instructions. All results arenormalized for a normal nasal protein/serum protein. Data obtainedbefore and after test article and control treatments are compared usingthe nonparametric Wilcoxon signed-rank test. A p-value <0.05 for thenull hypothesis was accepted as indicating a statistically significantdifference.

Generally, subjects treated with test article are expected to show asignificant improvement in nasal functions, symptom scores, analysis(blinded) of CT scans, and reduced nasal inflammatory cells relative tobaseline and control treatment.

Example 11 Assessment Therapeutic Effects

The following example illustrates methods for assessing the therapeuticeffects of a proinflammatory cytokine inhibitor (e.g., an IL-1inhibitor) on nonallergic upper airways inflammation.

An exploratory multi-center, double blind, placebo-controlled,randomized, phase 2 trial is performed with 240 acute sinusitis patientswith mild-to-moderate symptoms who receive 14 days of an oral quinoloneantibiotic at the initiation of the study. Thirty patients also receivedaily intranasal inhalation of anakinra (0.5 mg) for 28 days; anotherthirty patients receive daily intranasal inhalation of anakinra (0.5 mg)for 14 days following, one subcutaneous injection of anakinra (40 mg) 14days earlier (day 0) along with intranasal saline; another thirtypatients receive two subcutaneous injections of anakinra (40 mg) on day0 and day 14 with intranasal saline, and a fourth group of thirtypatient receive daily intranasal inhalation of saline daily from day 0through day 28. Thirty patients also receive daily intranasal inhalationof anakinra (0.5 mg) for 28 days and 500 mg of azithromicin daily forthe first three days; another thirty patients receive daily intranasalinhalation of anakinra (0.5 mg) for 14 days and 500 mg of azithromicindaily for the first three days following one subcutaneous injection ofanakinra (40 mg) 14 days earlier (day 0) along with intranasal saline;another thirty patients receive two subcutaneous injections of anakinra(40 mg) on day 0 and day 14 with intranasal saline and 500 mg ofazithromicin daily for the first three days, and a group of thirtypatients receive daily intranasal inhalation of saline daily from day 0through day 28.

Sinusitis is identified by history, clinical symptoms, and laboratoryfindings including abnormal. CT scans, and validated questionnaire.Nasal function parameters and side effects were evaluated. Allergicpredisposition is assessed by skin-prick tests performed with a standardpanel of 10 or more common airborne allergens (ALK, Copenhagen, Denmark)including pollen, house dust mites, mold, and animal allergens. Allsubjects with a positive skin for at least one allergen are consideredallergic and separated from nonallergic subjects during study. Steroidsare withheld for a minimum, of 6 weeks prior to and during the study.All studies are approved by the Institutional Review Board or EthicsCommittee as needed and an informed written consent is obtained fromeach subject.

Quantification of eosinophil and neutrophil numbers in nasal aspiratesare performed by counting numbers of human neutrophil elastase(HNE)-stained (for neutrophils) and EG2-stained (for eosinophils) cellsin a defined area of a defined volume of aspirate. Results are expressedas the average number of cells per volume of nasal lavage fluid

Quantification of cytokines is performed using commercially availableELISA methods as per the suppliers' instructions. All results arenormalized for a normal nasal protein/serum protein. Data obtainedbefore and after test article and control treatments are compared usingthe nonparametric Wilcoxon signed-rank test. A p-value <0.05 for thenull hypothesis was accepted as indicating a statistically significantdifference.

Generally, subjects treated with test article are expected to show asignificant improvement in nasal functions, symptom scores, analysis(blinded) of CT scans, and reduced nasal inflammatory cells relative tobaseline and control treatment.

Many modifications and variations of this invention can be made withoutdeparting from its spirit and scope, as will be apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only, and the invention is to be limited onlyby the terms of the appended claims along with the full scope ofequivalents to which such claims are entitled. All cited patents, patentapplications, and publications referred to in this application areherein incorporated by reference in their entirety.

1-25. (canceled)
 26. An aerosolizer comprising (i) means sized forintranasal or paranasal insertion that produces an aerosol from amaterial for delivery in close proximity to the upper airways, and (ii)the material comprising one or more proinflammatory cytokineinhibitor(s).
 27. The aerosolizer of claim 1, comprising a nasal sizedadapter, spray metering pump unit, a valve system, and a reservoir. 28.The aerosolizer of claim 1, comprising a nasal sized adapter, areservoir, a metering valve system, and a valve release mechanism whereactuation of the metering valve releases the material in close proximityto the upper airways.
 29. The aerosolizer of claim 1, wherein actuationof the metering valve releases the mixture as an aerosol, preferablycontaining particles in the size range of less than about 30 microns.30. The aerosolizer of claim 1, comprising a multi-dose system.
 31. Theaerosolizer of claim 1, comprising a closed multi-dose system.
 32. Theaerosolizer of claim 1, wherein the material is a liquid.
 33. Theaerosolizer of claim 1, wherein the material is dispersed using a jetnebulizer.
 34. The aerosolizer of claim 1, wherein the material is asuspension.
 35. The aerosolizer of claim 1, wherein the material isliquefied and under pressure.
 36. The aerosolizer of claim 1, whereinthe material is a powder.
 37. The aerosolizer of claim 1, whereindelivery of the aerosolized material is powered by mechanical pressuredriver apparatus.
 38. The aerosolizer of claim 1, wherein the deliveryof the aerosol material depends on energy from patient inspiration toopen a valve system providing access to the material.
 39. Theaerosolizer of claim 1, wherein a pressurized propellant powers thedelivery of the aerosol material.
 40. The aerosolizer of claim 1,wherein the delivery of the aerosol material is powered by a pressurizedcanister controlled by a one-way valve system allowing access to saidmaterial.
 41. A kit comprising a container, a label with instructions,and the aerosolizer of claim
 1. 42. The aerosolizer of claim 1,comprising a microcatheter for access and advancement into nasal cavityor paranasal sinuses, wherein the microcatheter comprises, at least oneflexible tubular communicating element with an outer diameter of 1500micron or less, with a distal end sized to fit within the tissue spaceand a proximal end connector shaped and sized to attach securely anddetachable from the aerosolizer.
 43. The aerosolizer of claim 1,comprising a microcatheter and a pressure driver apparatus, wherein afirst end of a hollow tube member of the microcatheter is of asufficient size so as to be able to enter fully or partially the nasalcavity or sinus, and a second end of the hollow tube member is connectedto the pressure driver apparatus, where activation of the pressuredriver apparatus delivers the material to the target upper airwayregion.
 44. The aerosolizer of claim 1, wherein the proinflammatorycytokine inhibitor is an IL-1 specific inhibitor.
 45. The aerosolizer ofclaim 1, wherein the proinflammatory cytokine inhibitor is Anakinra.